Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

ABSTRACT

This invention relates to novel 2,3-dihydroimidazo[1,2-c]quinazoline compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for phosphotidylinositol-3-kinase (PI3K) inhibition and treating diseases associated with phosphotidylinositol-3-kinase (PI3K) activity, in particular treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.

FIELD OF THE INVENTION

This invention relates to novel 2,3-dihydroimidazo[1,2-c]quinazolinecompounds, pharmaceutical compositions containing such compounds and theuse of those compounds or compositions for phosphotidylinositol-3-kinase(PI3K) inhibition and treating diseases associated withphosphotidylinositol-3-kinase (PI3K) activity, in particular treatinghyper-proliferative and/or angiogenesis disorders, as a sole agent or incombination with other active ingredients.

BACKGROUND OF THE INVENTION

In the last decade the concept of developing anti-cancer medicationswhich target abnormally active protein kinases has led to a number ofsuccesses. In addition to the actions of protein kinases, lipid kinasesalso play an important role in generating critical regulatory secondmessengers. The PI3K family of lipid kinases generates3′-phosphoinositides that bind to and activate a variety of cellulartargets, initiating a wide range of signal transduction cascades(Vanhaesebroeck et al., 2001; Toker, 2002; Pendaries et al., 2003;Downes et al., 2005). These cascades ultimately induce changes inmultiple cellular processes, including cell proliferation, cellsurvival, differentiation, vesicle trafficking, migration, andchemotaxis.

PI3Ks can be divided into three distinct classes based upon differencesin both structure, and substrate preference. While members of the ClassII family of PI3Ks have been implicated in the regulation of tumorgrowth (Brown and Shepard, 2001; Traer et al., 2006), the bulk ofresearch has focused on the Class I enzymes and their role in cancer(Vivanco And Sawyers, 2002; Workman, 2004, Chen et al., 2005; Hennesseyet al., 2005; Stauffer et al., 2005; Stephens et al., 2005; Cully etal., 2006).

Class I PI3Ks have traditionally been divided into two distinctsub-classes based upon differences in protein subunit composition. TheClass I_(A) PI3Ks are comprised of a catalytic p110 catalytic subunit(p110α, β or δ) heterodimerized with a member of the p85 regulatorysubunit family. In contrast, the Class I_(B) PI3K catalytic subunit(p110γ) heterodimerizes with a distinct p101 regulatory subunit(reviewed by Vanhaesebroeck and Waterfield, 1999; Funaki et al., 2000;Katso et al., 2001). The C-terminal region of these proteins contains acatalytic domain that possesses distant homology to protein kinases. ThePI3Kγ structure is similar to Class I_(A) p110s, but lacks theN-terminal p85 binding site (Domin and Waterfield, 1997). Though similarin overall structure, the homology between catalytic p110 subunits islow to moderate. The highest homology between the PI3K isoforms is inthe kinase pocket of the kinase domain.

The Class I_(A) PI3K isoforms associate with activated receptor tyrosinekinases (RTKs) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R andMet), or with tyrosine phosphorylated adapter proteins (such as Grb2,Cbl, IRS-1 or Gab1), via their p85 regulatory subunits resulting instimulation of the lipid kinase activity. Activation of the lipid kinaseactivity of the p110β and p110γ isoforms has been shown to occur inresponse to binding to activated forms of the ras Oncogene (Kodaki etal, 1994). In fact, the oncogenic activity of these isoforms may requirebinding to ras (Kang et al., 2006).

In contrast, the p110α and p110β isoforms exhibit oncogenic activityindependent of ras binding, through constitutive activation of Akt.

Class I PI3Ks catalyze the conversion of PI(4,5)P₂ [PIP₂] to PI(3,4,5)P₃[PIP₃]. The production of PIP₃ by PI3K affects multiple signalingprocesses that regulate and coordinate the biological end points of cellproliferation, cell survival, differentiation and cell migration. PIP₃is bound by Pleckstrin-Homology (PH) domain-containing proteins,including the phosphoinositide-dependent kinase, PDK1 and the Aktproto-oncogene product, localizing these proteins in regions of activesignal transduction and also contributing directly to their activation(Klippel et al., 1997; Fleming et al., 2000; Itoh and Takenawa, 2002;Lemmon, 2003). This co-localization of PDK1 with Akt facilitates thephosphorylation and activation of Akt. Carboxy-terminal phosphorylationof Akt on Ser⁴⁷³ promotes phosphorylation of Thr³⁰⁸ in the Aktactivation loop (Chan and Tsichlis, 2001; Hodgekinson et al., 2002;Scheid et al., 2002; Hresko et al., 2003). Once active, Aktphosphorylates and regulates multiple regulatory kinases of pathwaysthat directly influence cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated via its negativeregulation of pathways which impact cell survival and which are commonlydysregulated in cancer. Akt promotes tumor cell survival by regulatingcomponents of the apoptotic and cell cycle machinery. Akt is one ofseveral kinases that phosphorylate and inactivate pro-apoptotic BADproteins (del Paso et al., 1997; Pastorino et al., 1999). Akt may alsopromote cell survival through blocking cytochrome C-dependent caspaseactivation by phosphorylating Caspase 9 on Ser¹⁹⁶ (Cardone et al.,1998).

Akt impacts gene transcription on several levels. The Akt-mediatedphosphorylation of the MDM2 E3 ubiquitin ligase on Ser¹⁶⁶ and Ser¹⁸⁶facilitates the nuclear import of MDM2 and the formation and activationof the ubiquitin ligase complex. Nuclear MDM2 targets the p53 tumorsuppressor for degradation, a process that can be blocked by LY294002(Yap et al., 2000; Ogarawa et al., 2002). Downregulation of p53 by MDM2negatively impacts the transcription of p53-regulated pro-apoptoticgenes (e.g. Bax, Fas, PUMA and DR5), the cell cycle inhibitor,p21^(Cip1), and the PTEN tumor suppressor (Momand et al., 2000; Hupp etal., 2000; Mayo et al., 2002; Su et al., 2003). Similarly, theAkt-mediated phosphorylation of the Forkhead transcription factors FKHR,FKHRL and AFX (Kops et al., 1999; Tang et al., 1999), facilitates theirbinding to 14-3-3 proteins and export from the cell nucleus to thecytosol (Brunet et al., 1999). This functional inactivation of Forkheadactivity also impacts pro-apoptotic and pro-angiogenic genetranscription including the transcription of Fas ligand (Ciechomska etal., 2003) Bim, a pro-apoptotic Bcl-2 family member (Dijkers et al.,2000), and the Angiopoietin-1 (Ang-1) antagonist, Ang-2 (Daly et al.,2004). Forkhead transcription factors regulate the expression of thecyclin-dependent kinase (Cdk) inhibitor p27^(Kip1). Indeed, PI3Kinhibitors have been demonstrated to induce p27^(Kip1) expressionresulting in Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkerset al., 2000). Akt is also reported to phosphorylate p21^(Cip1) onThr¹⁴⁵ and p27^(Kip1) on Thr¹⁵⁷ facilitating their association with14-3-3 proteins, resulting in nuclear export and cytoplasmic retention,preventing their inhibition of nuclear Cdks (Zhou et al., 2001; Motti etal., 2004; Sekimoto et al., 2004). In addition to these effects, Aktphosphorylates IKK (Romashkova and Makarov, 1999), leading to thephosphorylation and degradation of IκB and subsequent nucleartranslocation of NFκB, resulting in the expression of survival genessuch as IAP and Bcl-X_(L).

The PI3K/Akt pathway is also linked to the suppression of apoptosisthrough the JNK and p38^(MAPK) MAP Kinases that are associated with theinduction of apoptosis. Akt is postulated to suppress JNK and p38^(MAPK)signaling through the phosphorylation and inhibition of two JNK/p38regulatory kinases, Apoptosis Signal-regulating Kinase 1 (ASK1) (Kim etal., 2001: Liao and Hung, 2003; Yuan et al., 2003), and Mixed LineageKinase 3 (MLK3) (Lopez-Ilasaca et al., 1997; Barthwal et al., 2003;Figueroa et al., 2003). The induction of p38^(MAPK) activity is observedin tumors treated with cytotoxic agents and is required for those agentsto induce cell death (reviewed by Olson and Hallahan, 2004). Thus,inhibitors of the PI3K pathway may promote the activities ofco-administered cytotoxic drugs.

An additional role for PI3K/Akt signaling involves the regulation ofcell cycle progression through modulation of Glycogen Synthase Kinase 3(GSK3) activity. GSK3 activity is elevated in quiescent cells, where itphosphorylates cyclin D₁ on Ser²⁸⁶, targeting the protein forubiquitination and degradation (Diehl et al., 1998) and blocking entryinto S-phase. Akt inhibits GSK3 activity through phosphorylation on Ser⁹(Cross et al., 1995). This results in the elevation of Cyclin D₁ levelswhich promotes cell cycle progression. Inhibition of GSK3 activity alsoimpacts cell proliferation through activation of the wnt/beta-cateninsignaling pathway (Abbosh and Nephew, 2005; Naito et al., 2005; Wilkeret al., 2005; Kim et al., 2006; Segrelles et al., 2006). Akt mediatedphosphorylation of GSK3 results in stabilization and nuclearlocalization of the beta-catenin protein, which in turn leads toincreased expression of c-myc and cyclin D1, targets of thebeta-catenin/Tcf pathway.

Although PI3K signaling is utilized by many of the signal transductionnetworks associated with both oncogenes and tumor suppressors, PI3K andits activity have been linked directly to cancer. Overexpression of boththe p110α and p110β isoforms has been observed in bladder and colontumors and cell lines, and overexpression generally correlates withincreased PI3K activity (Bénistant et al., 2000). Overexpression ofp110α has also been reported in ovarian and cervical tumors and tumorcell lines, as well as in squamous cell lung carcinomas. Theoverexpression of p110α in cervical and ovarian tumor lines isassociated with increased PI3K activity (Shayesteh et al., 1999; Ma etal., 2000). Elevated PI3K activity has been observed in colorectalcarcinomas (Phillips et al., 1998) and increased expression has beenobserved in breast carcinomas (Gershtein et al., 1999).

Over the last few years, somatic mutations in the gene encoding p110α(PIK3CA) have been identified in numerous cancers. The data collected todate suggests that PIK3CA is mutated in approximately 32% of colorectalcancers (Samuels et al., 2004; Ikenoue et al., 2005), 18-40% of breastcancers (Bachman et al., 2004; Campbell et al., 2004; Levine et al.,2005; Saal et al., 2005; Wu et al., 2005), 27% of glioblastomas (Samuelset al., 2004; Hartmann et al., 2005, Gallia et al., 2006), 25% ofgastric cancers (Byun et al., 2003; Samuels et al., 2004; Li et al.,2005), 36% of hepatocellular carcinomas (Lee et al., 2005), 4-12% ofovarian cancers (Levine et al., 2005; Wang et al., 2005), 4% of lungcancers (Samuels et al., 2004; Whyte and Holbeck, 2006), and up to 40%of endometrial cancers (Oda et al., 2005). PIK3CA mutations have beenreported in oligodendroma, astrocytoma, medulloblastoma, and thyroidtumors as well (Broderick et al., 2004; Garcia-Rostan et al., 2005).Based upon the observed high frequency of mutation, PIK3CA is one of thetwo most frequently mutated genes associated with cancer, the otherbeing K-ras. More than 80% of the PIK3CA mutations cluster within tworegions of the protein, the helical (E545K) and catalytic (H1047R)domains. Biochemical analysis and protein expression studies havedemonstrated that both mutations lead to increased constitutive p110αcatalytic activity and are in fact, oncogenic (Bader et al., 2006; Kanget al., 2005; Samuels et al., 2005; Samuels and Ericson, 2006).Recently, it has been reported that PIK3CA knockout mouse embryofibroblasts are deficient in signaling downstream from various growthfactor receptors (IGF-1, Insulin, PDGF, EGF), and are resistant totransformation by a variety of oncogenic RTKs (IGFR, wild-type EGFR andsomatic activating mutants of EGFR, Her2/Neu) (Zhao et al., 2006).

Functional studies of PI3K in vivo have demonstrated that siRNA-mediateddownregulation of p110β inhibits both Akt phosphorylation and HeLa celltumor growth in nude mice (Czauderna et al., 2003). In similarexperiments, siRNA-mediated downregulation of p110β was also shown toinhibit the growth of malignant glioma cells in vitro and in vivo (Pu etal., 2006). Inhibition of PI3K function by dominant-negative p85regulatory subunits can block mitogenesis and cell transformation (Huanget al., 1996; Rahimi et al., 1996). Several somatic mutations in thegenes encoding the p85α and p85β regulatory subunits of PI3K that resultin elevated lipid kinase activity have been identified in a number ofcancer cells as well (Janssen et al., 1998; Jimenez et al., 1998; Philpet al., 2001; Jucker et al., 2002; Shekar et al., 2005). NeutralizingPI3K antibodies also block mitogenesis and can induce apoptosis in vitro(Roche et al., 1994: Roche et al., 1998; Bénistant et al., 2000). Invivo proof-of-principle studies using the PI3K inhibitors LY294002 andwortmannin, demonstrate that inhibition of PI3K signaling slows tumorgrowth in vivo (Powis et al., 1994; Shultz et al., 1995; Semba et al.,2002; Ihle et al., 2004).

Overexpression of Class I PI3K activity, or stimulation of their lipidkinase activities, is associated with resistance to both targeted (suchas imatinib and tratsuzumab) and cytotoxic chemotherapeutic approaches,as well as radiation therapy (West et al., 2002; Gupta et al., 2003;Osaki et al., 2004; Nagata et al., 2004; Gottschalk et al., 2005; Kim etal., 2005). Activation of PI3K has also been shown to lead to expressionof multidrug resistant protein-1 (MRP-1) in prostate cancer cells andthe subsequent induction of resistance to chemotherapy (Lee et al.,2004).

The importance of PI3K signaling in tumorigenesis is further underscoredby the findings that the PTEN tumor suppressor, a PI(3)P phosphatase, isamong the most commonly inactivated genes in human cancers (Li et al.,1997, Steck et al., 1997; Ali et al., 1999; Ishii et al., 1999). PTENdephosphorylates PI(3,4,5)P₃ to PI(4,5)P₂ thereby antagonizingPI3K-dependent signaling. Cells containing functionally inactive PTENhave elevated levels of PIP₃, high levels of activity of PI3K signaling(Haas-Kogan et al., 1998; Myers et al., 1998; Taylor et al., 2000),increased proliferative potential, and decreased sensitivity topro-apoptotic stimuli (Stambolic et al., 1998). Reconstitution of afunctional PTEN suppresses PI3K signaling (Taylor et al., 2000),inhibits cell growth and re-sensitizes cells to pro-apoptotic stimuli(Myers et al., 1998; Zhao et al., 2004). Similarly, restoration of PTENfunction in tumors lacking functional PTEN inhibits tumor growth in vivo(Stahl et al., 2003; Su et al., 2003; Tanaka and Grossman, 2003) andsensitizes cells to cytotoxic agents (Tanaka and Grossman, 2003).

The class I family of PI3Ks clearly plays an important role in theregulation of multiple signal transduction pathways that promote cellsurvival and cell proliferation, and activation of their lipid kinaseactivity contributes significantly to the development of humanmalignancies. Furthermore, inhibition of PI3K may potentially circumventthe cellular mechanisms that underlie resistance to chemotherapeuticagents. A potent inhibitor of Class I PI3K activities would thereforehave the potential not only to inhibit tumor growth but to alsosensitize tumor cells to pro-apoptotic stimuli in vivo.

Signal transduction pathways originating from chemoattractant receptorsare considered to be important targets in controlling leukocyte motilityin inflammatory diseases. Leukocyte trafficking is controlled bychemoattractant factors that activate heterotrimeric GPCRs and therebytrigger a variety of downstream intracellular events. Signaltransduction along one of these pathways that results in mobilization offree Ca²⁺, cytoskelatal reorganization, and directional movement dependson lipid-derived second messengers producted by PI3K activity (Wymann etal., 2000; Stein and Waterfield, 2000).

PI3Kγ modulates baseline cAMP levels and controls contractility incells. Recent research indicates that alterations in baseline cAMPlevels contributes to the increased contractility in mutant mice. Thisresearch, therefore, shows that PI3Kγ inhibitors would afford potentialtreatments for congestive heart failure, ischemia, pulmonaryhypertension, renal failure, cardiac hypertrophy, atherosclerosis,thromboembolism, and diabetes.

PI3K inhibitors would be expected to block signal transduction fromGPCRs and block the activation of various immune cells, leading to abroad anti-inflammatory profile with potential for the treatment ofinflammatory and immunoregulatory diseases, including asthma, atopicdermatitis, rhinitis, allergic diseases, chronic obstructive pulmonarydisease (COPD), septic shock, joint diseases, autoimmune pathologiessuch as rheumatoid arthritis and Graves' disease, diabetes, cancer,myocardial contractility disorders, thromboembolism, andatherosclerosis.

PI3K inhibitor compounds and compositions described herein, includingsalts, metabolites, solvates, solvates of salts, hydrates, andstereoisomeric forms thereof, exhibit anti-proliferative activity andare thus useful to prevent or treat the disorders associated withhyper-proliferation.

DESCRIPTION OF THE INVENTION

One embodiment of this invention encompasses a compound having theformula (I):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein:

-   -   R¹ is —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R⁵);    -   R² is a heteroaryl optionally substituted with 1, 2 or 3 R⁶        groups;    -   R³ is alkyl or cycloalkyl;    -   R⁴ is hydrogen, hydroxy or alkoxy and R⁵ and R^(5′) may be the        same or different and are independently, hydrogen, alkyl,        cycloalkylalklyl, or alkoxyalkyl or R⁵ and R^(5′) may be taken        together with the nitrogen atom to which they are bound to form        a 3-7 membered nitrogen containing heterocyclic ring optionally        containing at least one additional heteroatom selected from        oxygen, nitrogen or sulfur and which may be optionally        substituted with 1 or more R^(6′) groups, or R⁴ and R⁵ may be        taken together with the atoms to which they are bound to form a        5-6 membered nitrogen containing heterocyclic ring optionally        containing 1 or more nitrogen, oxygen or sulfur atoms and which        may be optionally substituted with 1 or more R^(6′) groups;

each occurrence of R⁶ may be the same or different and is independentlyhalogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalklyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring,heterocyclylalkyl, alkyl-OR⁷, alkyl-SR⁷, alkyl-N(R⁷)(R^(7′)),alkyl-COR⁷, —CN, —COOR⁷, —CON(R⁷)(R^(7′)), —OR⁷, —SR⁷, —N(R⁷)(R^(7′)),or —NR⁷COR⁷ each of which may be optionally substituted with 1 or moreR⁸ groups;

each occurrence of R^(6′) may be the same or different and isindependently alkyl, cycloalkylalklyl, or alkyl-OR⁷;

each occurrence of R⁷ and R^(7′) may be the same or different and isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;

each occurrence of R⁸ is independently nitro, hydroxy, cyano, formyl,acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;

n is an integer from 1-4 and m is an integer from 0-4 with the provisothat when R⁴ and R⁵ are taken together with the atoms to which they arebound to form a 5-6 membered nitrogen containing ring, n+m≦4.

In a preferred embodiment, the invention encompasses the compound ofFormula (I), wherein R² is a nitrogen containing heteroaryl optionallysubstituted with 1, 2 or 3 R⁶ groups.

In another preferred embodiment, the invention encompasses the compoundof Formula (I), wherein R⁵ and R^(5′) are independently alkyl;

In still another preferred embodiment, the invention encompasses thecompound of Formula (I), wherein R⁵ and R⁵ are taken together with thenitrogen atom to which they are bound to form a 5-6 membered nitrogencontaining heterocyclic ring containing at least one additionalheteroatom selected from oxygen, nitrogen or sulfur and which may beoptionally substituted with 1 or more R^(6′) groups.

In yet another preferred embodiment, the invention encompasses thecompound of Formula (I), wherein R⁴ is hydroxy.

In another preferred embodiment, the invention encompasses the compoundof Formula (I), wherein R⁴ and R⁵ are taken together with the atoms towhich they are bound to form a 5-6 membered nitrogen containingheterocyclic ring optionally containing 1 or more nitrogen, oxygen orsulfur atoms and which may be optionally substituted with 1 or more R⁶groups.

In yet another preferred embodiment, the invention encompasses thecompound of Formula (I), wherein R³ is methyl.

In still another preferred embodiment, the invention encompasses thecompound of Formula (I), wherein R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole, thiazole, furan or thiophene, optionallysubstituted with 1, 2 or 3 R⁶ groups; more preferably pyridine,pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups.

In a distinct embodiment, the invention encompasses a compound offormula (Ia)

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above.

In another distinct embodiment, the invention encompasses a compound offormula (Ib)

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above.

In still another distinct embodiment, the invention encompasses acompound of formula (Ic)

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above.

In yet another distinct embodiment, the invention encompasses a compoundof the formula (Id):

-   -   or a physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof, wherein R² and R⁴ are as defined above.

In yet another distinct embodiment, the invention encompasses a compoundof the formula (Ie):

-   -   or a physiologically acceptable salt, solvate, hydrate or        stereoisomer thereof, wherein R² and R⁴ are as defined above.

In a preferred embodiment, the invention encompasses a compound offormula (I)-(V), wherein R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole, thiazole, furan or thiophene, optionallysubstituted with 1, 2 or 3 R⁶ groups; more preferrably wherein R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups.

In still another preferred embodiment, the invention encompasses acompound having the formula:

-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide;-   N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;-   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide    1-oxide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;-   6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[8-(2-hydroxy-3-morpholin-4-ylpropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{7-methoxy-8-[3-(3-methyl    morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(8-{2-[4-(cyclobutylmethyl)morpholin-2-yl]ethoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-(7-methoxy-8-{2-[4-(2-methoxyethyl)morpholin-2-yl]ethoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-{8-[(4-ethylmorpholin-2-yl)methoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-(7-methoxy-8-{[4-(2-methoxyethyl)morpholin-2-yl]methoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-{7-methoxy-8-[(4-methyl    morpholin-2-yl)methoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-4-carboxamide;-   rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;-   rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-6-methylnicotinamide;-   rel-6-acetamido-N-(8-{3-[(2R,6S)-2,6-dimethyl    morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-5-carboxamide;-   6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methyl    nicotinamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methylpyrimidine-5-carboxamide;-   6-amino-5-bromo-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-5-carboxamide;-   N-[7-methoxy-8-(morpholin-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   2-{[2-(dim    ethylamino)ethyl]amino}-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;-   2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-1,3-thiazole-5-carboxamide;-   rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethyl    morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;-   rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethyl    morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   2-[(2-hydroxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-methoxypropyl)amino]pyrimidine-5-carboxamide;-   2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-morpholin-4-ylpropyl)amino]pyrimidine-5-carboxamide;-   2-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   6-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-pyrrolidin-1-ylpyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-morpholin-4-ylpyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-piperazin-1-ylnicotinamide    hydrochloride;-   6-[(3S)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide    hydrochloride hydrate;-   6-[(3R)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide    hydrochloride;-   6-[(4-fluorobenzyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-[(2-furylmethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(1H-pyrrol-1-yl)nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-morpholin-4-ylnicotinamide;-   N-{7-methoxy-8-[3-(methylamino)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2,2,2-trifluoroethoxy)nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(trifluoromethyl)nicotinamide;-   6-(isobutyrylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{7-methoxy-8-[3-(4-methylpiperazin-1-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-{[(methylamino)carbonyl]amino}-1,3-thiazole-4-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-{[(methylamino)carbonyl]amino}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)-1,3-thiazole-4-carboxamide;-   N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-6-methylnicotinamide;-   6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-pyrrolidin-1-ylnicotinamide;-   6-(dimethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-piperidin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(2-pyrrolidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(2-piperidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-{[(ethylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-fluoro-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-4-carboxamide;-   2-(ethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-4-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrazine-2-carboxamide;-   N-[8-(2-aminoethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;-   N-{8-[3-(diethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[2-(diisopropylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[2-(diethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylthio)pyrimidine-5-carboxamide;-   N-[8-(3-aminopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide    trifluoroacetate;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-2-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   2-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-3-furamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-3-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methyl-1,3-thiazole-4-carboxamide;-   6-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;-   6-(acetylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    or a physiologically acceptable salt, solvate, hydrate or    stereoisomer thereof.

In a preferred embodiment, the invention encompasses a compound havingthe formula:

-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;-   5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;-   6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;-   rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;-   rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;-   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;-   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;-   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    or a physiologically acceptable salt, solvate, hydrate or    stereoisomer thereof.

Where there is a discrepancy between the chemical name and the chemicalstructure depicted, the chemical structure depicted takes precedenceover the chemical name given.

Without being bound by theory or mechanism, the compounds of the presentinvention display surprising activity for the inhibition ofphosphatidylinositol-3-kinase and chemical and structural stability overthose compounds of the prior art. It is believed that this surprisingactivity is based on the chemical structure of the compounds, inparticular the basicity of the compounds as a result of R¹ being aminooptionally substituted with R⁵ and R^(5′). Further, the appropriatechoice of R³ and R² provide the necessary activity against theappropriate isoforms to allow for activity in vivo.

Definitions

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containingsolely of carbon and hydrogen atoms, containing no unsaturation, havingfrom one to eight carbon atoms, and which is attached to the rest of themolecule by a single bond, such as illustratively, methyl, ethyl,n-propyl 1-methylethyl(isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl(t-butyl). The term “alkenyl” refers to an aliphatichydrocarbon group containing a carbon-carbon double bond and which maybe a straight or branched or branched chain having about 2 to about 10carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl(allyl),iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2- and butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbonylradicals having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with radicals having in therange of about 2 up to 10 carbon atoms presently being preferred) e.g.,ethynyl.

The term “alkoxy” denotes an alkyl group as defined herein attached viaoxygen linkage to the rest of the molecule. Representative examples ofthose groups are methoxy and ethoxy.

The term “alkoxyakyl” denotes an alkoxy group as defined herein attachedvia oxygen linkage to an alkyl group which is then attached to the mainstructure at any carbon from alkyl group that results in the creation ofa stable structure the rest of the molecule. Representative examples ofthose groups are —CH₂OCH₃, —CH₂OC₂H₅.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups bridged cyclicgroup or sprirobicyclic groups e.g sprio (4,4) non-2-yl.

The term “cycloalkylalkyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms directlyattached to alkyl group which is then also attached to the mainstructure at any carbon from the alkyl group that results in thecreation of a stable structure such as cyclopropylmethyl,cyclobuyylethyl, cyclopentylethyl.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl,biphenyl.

The term “arylalkyl” refers to an aryl group as defined herein directlybonded to an alkyl group as defined herein which is then attached to themain structure at any carbon from alkyl group that results in thecreation of a stable structure the rest of the molecule. e.g., —CH₂C₆H₅,—C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a stable 3- to 15 membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a monocyclic, bicyclic or tricyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical may be optionally oxidized to various oxidation states. Inaddition, the nitrogen atom may be optionally quaternized; and the ringradical may be partially or fully saturated (i.e., heteroaromatic orheteroaryl aromatic). Examples of such heterocyclic ring radicalsinclude, but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofurnyl, carbazolyl cinnolinyl dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinylpyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl,isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinylsulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl.

The term “heteroaryl” refers to heterocyclic ring radical as definedherein which are aromatic. The heteroaryl ring radical may be attachedto the main structure at any heteroatom or carbon atom that results inthe creation of a stable structure.

The heterocyclic ring radical may be attached to the main structure atany heteroatom or carbon atom that results in the creation of a stablestructure.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedherein directly bonded to alkyl group. The heteroarylalkyl radical maybe attached to the main structure at any carbon atom from alkyl groupthat results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedherein. The heterocylyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined herein directly bonded to alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “carbonyl” refers to an oxygen atom bound to a carbon atom ofthe molecule by a double bond.

The term “halogen” refers to radicals of fluorine, chlorine, bromine andiodine.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

The compounds of this invention may contain one or more asymmetriccenters, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric center, and diastereomeric mixtures in the case ofmultiple asymmetric centers. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds. Substituents on a ring may also be present in either cis ortrans form. It is intended that all such configurations (includingenantiomers and diastereomers), are included within the scope of thepresent invention. Preferred compounds are those, which produce the moredesirable biological activity. Separated, pure or partially purifiedisomers and stereoisomers or racemic or diastereomeric mixtures of thecompounds of this invention are also included within the scope of thepresent invention. The purification and the separation of such materialscan be accomplished by standard techniques known in the art.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts,co-precipitates, metabolites, hydrates, solvates and prodrugs of all thecompounds of examples. The term “pharmaceutically acceptable salt”refers to a relatively non-toxic, inorganic or organic acid additionsalt of a compound of the present invention. For example, see S. M.Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base, with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid and citric acid. Pharmaceuticallyacceptable salts also include those in which the main compound functionsas an acid and is reacted with an appropriate base to form, e.g.,sodium, potassium, calcium, magnesium, ammonium, and chorine salts.Those skilled in the art will further recognize that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide,iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate,mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate,thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, or butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and strearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others.

A solvate for the purpose of this invention is a complex of a solventand a compound of the invention in the solid state. Exemplary solvateswould include, but are not limited to, complexes of a compound of theinvention with ethanol or methanol. Hydrates are a specific form ofsolvate wherein the solvent is water.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilized to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug.

Such materials are, for example, cocoa butter and polyethylene glycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52 (5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53 (6), 324-349;and Nema, S. et al, “Excipients and Their Use in Injectable Products”PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4),166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC-CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.

Lyophilized Powder for IV Administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular Suspension: The following solution or suspension can beprepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumors,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant kinase activity (such as tyrosinekinase activity), including, phosphotidylinositol-3-kinase.

Effective amounts of compounds of the present invention can be used totreat disorders, including angiogenic disorders, such as cancer;inflammatory disorders (including but not limited to Chronic obstructivepulmonary disorder (COPD)), autoimmune disorders, cardiovasculardisorders (including but not limited to thrombosis, pulmonaryhypertension, cardiac hypertophy, atherosclerosis or heart failure),neurodegenerative disorders, metabolic disorders, nociceptive disorders,ophthalmic disorders, pulmonary disorders, or renal disorders.Nonetheless, such cancers and other diseases can be treated withcompounds of the present invention, regardless of the mechanism ofaction and/or the relationship between the kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of phosphotidylinositol-3-kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hyrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855),neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumor enlargement and metastasis. Moreover, thegrowth of new blood and lymph vessels in a tumor provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with known anti-hyper-proliferative, antiinflammatory,analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviralagents, and the like, as well as with admixtures and combinationsthereof.

The additional pharmaceutical agent can be aldesleukin, alendronic acid,alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine,aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole,anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine,azathioprine, BCG or tice BCG, bestatin, betamethasone acetate,betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol,etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim,finasteride, fligrastim, floxuridine, fluconazole, fludarabine,5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lentinan sulphate, letrozole, leucovorin,leuprolide, leuprolide acetate, levamisole, levofolinic acid calciumsalt, levothroid, levoxyl, lomustine, lonidamine, marinol,mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrolacetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate,metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide,nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin,picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab,roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine,sizofuran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin,tasonermin, tastolactone, taxotere, teceleukin, temozolomide,teniposide, testosterone propionate, testred, thioguanine, thiotepa,thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine,valrubicin, vesnarinone, vinblastine, vincristine, vindesine,vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran,ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene,asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin,CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate,decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,eflornithine, exatecan, fenretinide, histamine dihydrochloride,histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene,minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin,neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxelpolyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549,raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol,T-138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine,tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar,vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acidor combinations thereof.

The additional pharmaceutical agent can also be gemcitabine, paclitaxel,cisplatin, carboplatin, sodium butyrate, 5-FU, doxirubicin, tamoxifen,etoposide, trastumazab, gefitinib, intron A, rapamycin, 17-AAG, U0126,insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug, anα-glucosidase inhibitor, a biguanide, a PTP-1B inhibitor, a DPP-IVinhibitor, a 11-beta-HSD inhibitor, GLP-1, a GLP-1 derivative, GIP, aGIP derivative, PACAP, a PACAP derivative, secretin or a secretinderivative.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemo-therapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

EXPERIMENTAL

Abbreviations and Acronyms

A comprehensive list of the abbreviations used by organic chemists ofordinary skill in the art appears in The ACS Style Guide (third edition)or the Guidelines for Authors for the Journal of Organic Chemistry. Theabbreviations contained in said lists, and all abbreviations utilized byorganic chemists of ordinary skill in the art are hereby incorporated byreference. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

More specifically, when the following abbreviations are used throughoutthis disclosure, they have the following meanings:

acac acetylacetonate Ac₂O acetic anhydride AcO (or OAc) acetate anhydanhydrous aq aqueous Ar aryl atm atmosphere 9-BBN9-borabicyclo[3.3.1]nonyl BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphthyl Bn benzyl bp boiling pointbr s broad singlet Bz benzoyl BOC tert-butoxycarbonyl n-BuOH n-butanolt-BuOH tert-butanol t-BuOK potassium tert-butoxide C Celsius calcdcalculated CAN ceric ammonium nitrate Cbz carbobenzyloxy CDI carbonyldiimidazole CD₃OD methanol-d₄ Celite ® diatomaceous earth filter agent,Celite ® Corp. CI-MS chemical ionization mass spectroscopy ¹³C NMRcarbon-13 nuclear magnetic resonance m-CPBA meta-chloroperoxybenzoicacid d doublet dd doublet of doublets DABCO1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCCN,N′-dicyclohexylcarbodiimide DCM dichloromethane DEAD diethylazodicarboxylate dec decomposition DIA diisopropylamine DIBALdiisobutylaluminum hydride DMAP 4-(N,N-dimethylamino)pyridine DME1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide Eentgegen (configuration) EDCI or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDCI•HCl hydrochloride eeenantiomeric excess EI electron impact ELSD evaporative light scatteringdetector equiv equivalent ES-MS electrospray mass spectroscopy EtOAcethyl acetate EtOH ethanol (100%) EtSH ethanethiol Et₂O diethyl etherEt₃N triethylamine Fmoc 9-fluorenylmethoxycarbonyl GC gas chromatographyGC-MS gas chromatography-mass spectroscopy h hour, hours hex hexanes, orhexane ¹H NMR proton nuclear magnetic resonance HMPAhexamethylphosphoramide HMPT hexamethylphosphoric triamide HOBThydroxybenzotriazole HPLC high performance liquid chromatography insolinsoluble IPA isopropylamine iPrOH isopropylalcohol IR infrared Jcoupling constant (NMR spectroscopy) L liter LAH lithium aluminumhydride LC liquid chromatography LC-MS liquid chromatography-massspectrometry LDA lithium diisopropylamide M mol L⁻¹ (molar) m multipletm meta MeCN acetonitrile MeOH methanol MHz megahertz min minute, minutesμL microliter mL milliliter μM micromolar mol mole mp melting point MSmass spectrum, mass spectrometry Ms methanesulfonyl m/z mass-to-chargeratio N equiv L⁻¹ (normal) NBS N-bromosuccinimide nM nanomolar NMM4-methylmorpholine NMR Nuclear Magnetic Resonance o ortho obsd observedp para p page pp pages PdCl₂dppf[1,1′-bis(diphenylphosphino)ferrocene]dichloro- palladium(II) Pd(OAc)₂palladium acetate pH negative logarithm of hydrogen ion concentration Phphenyl pK negative logarithm of equilibrium constant pK_(a) negativelogarithm of equilibrium constant for association PPA poly(phosphoricacid) PS-DIEA Polystyrene-bound diisopropylethylamine PyBOPbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphateq quartet rac racemic R rectus (configurational) R_(f) retardationfactor (TLC) RT retention time (HPLC) rt room temperature s singlet Ssinister (configurational) t triplet TBDMS, TBP tert-butyldimethylsilylTBDPS, TPS tert-butyldiphenylsilyl TEA triethylamine THF tetrahydrofuranTf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFFHFluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate TLC thinlayer chromatography TMAD N,N,N′,N′-tetramethylethylenediamine TMSCltrimethylsilyl chloride Ts p-toluenesulfonyl v/v volume to volume ratiow/v weight to volume ratio w/w weight to weight ratio Z zusammen(configuration)

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar amount. Air andmoisture sensitive liquids and solutions were transferred via syringe orcannula, and introduced into reaction vessels through rubber septa.Commercial grade reagents and solvents were used without furtherpurification. The term “concentrated under reduced pressure” refers touse of a Buchi rotary evaporator at approximately 15 mm of Hg. Alltemperatures are reported uncorrected in degrees Celsius (° C.). Thinlayer chromatography (TLC) was performed on pre-coated glass-backedsilica gel 60 A F-254 250 μm plates.

The structures of compounds of this invention were confirmed using oneor more of the following procedures.

NMR

NMR spectra were acquired for each compound and were consistent with thestructures shown.

Routine one-dimensional NMR spectroscopy was performed on either 300 or400 MHz Varian Mercury-plus spectrometers. The samples were dissolved indeuterated solvents. Chemical shifts were recorded on the ppm scale andwere referenced to the appropriate solvent signals, such as 2.49 ppm forDMSO-d6, 1.93 ppm for CD3CN, 3.30 ppm for CD3OD, 5.32 ppm for CD2Cl2 and7.26 ppm for CDCl3 for 1H spectra.

GC/MS

Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard 5973 mass spectrometer equipped Hewlett Packard 6890 GasChromatograph with a J & W HP-5 column (0.25 uM coating; 30 m×0.32 mm).The ion source was maintained at 250° C. and spectra were scanned from50-550 amu at 0.34 sec per scan.

LC/MS

Unless otherwise noted, all retention times are obtained from the LC/MSand correspond to the molecular ion. High pressure liquidchromatography-electrospray mass spectra (LC/MS) were obtained using oneof the following:

Method A (LCQ)

Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variablewavelength detector set at 254 nm, a Waters Sunfire C18 column (2.1×30mm, 3.5 m), a Gilson autosampler and a Finnigan LCQ ion trap massspectrometer with electrospray ionization. Spectra were scanned from120-1200 amu using a variable ion time according to the number of ionsin the source. The eluents were A: 2% acetonitrile in water with 0.02%TFA, and B: 2% water in acetonirile with 0.018% TFA. Gradient elutionfrom 10% B to 95% B over 3.5 minutes at a flow rate of 1.0 mL/min wasused with an initial hold of 0.5 minutes and a final hold at 95% B of0.5 minutes. Total run time was 6.5 minutes.

Method B (LCQ5)

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, a variable wavelengthdetector set at 254 nm. The HPLC column used was a Waters Sunfire C-18column (2.1×30 mm, 3.5 μm). The HPLC eluent was directly coupled withoutsplitting to a Finnigan LCQ DECA ion trap mass spectrometer withelectrospray ionization. Spectra were scanned from 140-1200 amu using avariable ion time according to the number of ions in the source usingpositive ion mode. The eluents were A: 2% acetonitrile in water with0.02% TFA, and B: 2% water in acetonirile with 0.02% TFA. Gradientelution from 10% B to 90% B over 3.0 minutes at a flow rate of 1.0mL/min was used with an initial hold of 1.0 minutes and a final hold at95% B of 1.0 minutes. Total run time was 7.0 minutes.

Method C (LTQ)

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, and a diode array. TheHPLC column used was a Waters Sunfire C18 column (2.1×30 mm, 3.5 μm).The HPLC eluent was directly coupled with a 1:4 split to a Finnigan LTQion trap mass spectrometer with electrospray ionization. Spectra werescanned from 50-800 amu using a variable ion time according to thenumber of ions in the source using positive or negative ion mode. Theeluents were A: water with 0.1 formic acid, and B: acetonitrile with0.1% formic acid. Gradient elution from 10% B to 90% B over 3.0 minutesat a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutesand a final hold at 95% B of 1.0 minutes. Total run time was 8.0minutes.

Method D

Gilson HPLC system equipped with a variable wavelength detector set at254 nm, a YMC pro C-18 column (2×23 mm, 120 A), and a Finnigan LCQ iontrap mass spectrometer with electrospray ionization. Spectra werescanned from 120-1200 amu using a variable ion time according to thenumber of ions in the source. The eluants were A: 2% acetonitrile inwater with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA.Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of1.0 mL/min was used with an initial hold of 0.5 minutes and a final holdat 95% B of 0.5 minutes. Total run time was 6.5 minutes.

Method E

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, and a diode array. TheHPLC column used was a Waters Sunfire (2.1×30 mm, 3.5 μm). The HPLCeluent was directly coupled with a 1:4 split to a Finnigan LTQ ion trapmass spectrometer with electrospray ionization. Spectra were scannedfrom 50-1000 amu using a variable ion time according to the number ofions in the source in either positive or negative ion mode. The eluentswere A: water with 0.1 formic acid, and B: acetonirile with 0.1% formicacid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and afinal hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.

Preparative HPLC:

Preparative HPLC was carried out in reversed phase mode, typically usinga Gilson HPLC system equipped with two Gilson 322 pumps, a Gilson 215Autosampler, a Gilson diode array detector, and a C-18 column (e.g. YMCPro 20×150 mm, 120 A). Gradient elution was used with solvent A as waterwith 0.1% TFA, and solvent B as acetonitrile with 0.1% TFA. Followinginjection onto the column as a solution, the compound was typicallyeluted with a mixed solvent gradient, such as 10-90% Solvent B inSolvent A over 15 minutes with flow rate of 25 mL/min. The fraction(s)containing the desired product were collected by UV monitoring at 254 or220 nm.

Preparative MPLC:

Preparative medium pressure liquid chromatography (MPLC) was carried outby standard silica gel “flash chromatography” techniques (e.g., Still,W. C. et al. J. Org. Chem. 1978, 43, 2923-5), or by using silica gelcartridges and devices such as the Biotage Flash systems. A variety ofeluting solvents were used, as described in the experimental protocols.

General Preparative Methods

The particular process to be utilized in the preparation of thecompounds used in this embodiment of the invention depends upon thespecific compound desired. Such factors as the selection of the specificsubstituents play a role in the path to be followed in the preparationof the specific compounds of this invention. Those factors are readilyrecognized by one of ordinary skill in the art.

The compounds of the invention may be prepared by use of known chemicalreactions and procedures. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing thecompounds of the present invention, with more detailed particularexamples being presented below in the experimental section describingthe working examples.

The compounds of the invention can be made according to conventionalchemical methods, and/or as disclosed below, from starting materialswhich are either commercially available or producible according toroutine, conventional chemical methods. General methods for thepreparation of the compounds are given below, and the preparation ofrepresentative compounds is specifically illustrated in examples.

Synthetic transformations that may be employed in the synthesis ofcompounds of this invention and in the synthesis of intermediatesinvolved in the synthesis of compounds of this invention are known by oraccessible to one skilled in the art. Collections of synthetictransformations may be found in compilations, such as:

-   J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New    York (1992) R. C. Larock. Comprehensive Organic Transformations, 2nd    ed.; Wiley-VCH: New York (1999)-   F. A. Carey; R. J. Sundberg. Advanced Organic Chemistry, 2nd ed.;    Plenum Press: New York (1984)-   T. W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis,    3rd ed.; John Wiley: New York (1999)-   L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic    Molecules, 2nd ed.; University Science Books: Mill Valley, Calif.    (1994)-   L. A. Paquette, Ed. The Encyclopedia of Reagents for Organic    Synthesis; John Wiley: New York (1994)-   A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds. Comprehensive    Organic Functional Group Transformations; Pergamon Press: Oxford, UK    (1995)-   G. Wilkinson; F. G A. Stone; E. W. Abel, Eds. Comprehensive    Organometallic Chemistry; Pergamon Press: Oxford, UK (1982)-   B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon    Press: Oxford, UK (1991)-   A. R. Katritzky; C. W. Rees Eds. Comprehensive Heterocylic    Chemistry; Pergamon Press: Oxford, UK (1984)-   A. R. Katritzky; C. W. Rees; E. F. V. Scriven, Eds. Comprehensive    Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996)-   C. Hansch; P. G. Sammes; J. B. Taylor, Eds. Comprehensive Medicinal    Chemistry: Pergamon Press: Oxford, UK (1990).

In addition, recurring reviews of synthetic methodology and relatedtopics include Organic Reactions; John Wiley: New York; OrganicSyntheses; John Wiley: New York; Reagents for Organic Synthesis: JohnWiley: New York; The Total Synthesis of Natural Products; John Wiley:New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York;Annual Reports in Organic Synthesis; Academic Press: San Diego Calif.;and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart,Germany. Furthermore, databases of synthetic transformations includeChemical Abstracts, which may be searched using either CAS OnLine orSciFinder, Handbuch der Organischen Chemie (Beilstein), which may besearched using SpotFire, and REACCS.

In Reaction Scheme 1, vanillin acetate can be converted to intermediate(III) via nitration conditions such as neat fuming nitric acid or nitricacid in the presence of another strong acid such as sulfuric acid.Hydrolysis of the acetate in intermediate (III) would be expected in thepresence of bases such as sodium hydroxide, lithium hydroxide, orpotassium hydroxide in a protic solvent such as methanol. Protection ofintermediate (IV) to generate compounds of Formula (V) could beaccomplished by standard methods (Greene, T. W.; Wuts, P. G. M.;Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999).Conversion of compounds of formula (V) to those of formula (VI) can beachieved using ammonia in the presence of iodine in an aprotic solventsuch as THF or dioxane. Reduction of the nitro group in formula (VI)could be accomplished using iron in acetic acid or hydrogen gas in thepresence of a suitable palladium, platinum or nickel catalyst.Conversion of compounds of formula (VII) to the imidazoline of formula(VIII) is best accomplished using ethylenediamine in the presence of acatalyst such as elemental sulfur with heating. The cyclization ofcompounds of formula (VIII) to those of formula (IX) is accomplishedusing cyanogen bromide in the presence of an amine base such astriethylamine, diisopropylethylamine, or pyridine in a halogenatedsolvent such as DCM or dichloroethane. Removal of the protecting groupin formula (IX) will be dependent on the group selected and can beaccomplished by standard methods (Greene, T. W.; Wuts, P. G. M.;Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999).Alkylation of the phenol in formula (X) can be achieved using a basesuch as cesium carbonate, sodium hydride, or potassium t-butoxide in apolar aprotic solvent such as DMF or DMSO with introduction of a sidechain bearing an appropriate leaving group such as a halide, or asulfonate group. Lastly, amides of formula (I) can be formed usingactivated esters such as acid chlorides and anhydrides or alternativelyformed using carboxylic acids and appropriate coupling agents such asPYBOP, DCC, or EDCI in polar aprotic solvents.

In Reaction Scheme 2, a compound of formula (IV), prepared as describedabove, can be converted to a structure of formula (XII) using ammonia inthe presence of iodine in an aprotic solvent such as THF or dioxane.Alkylation of the phenol in formula (XII) can be achieved using a basesuch as cesium carbonate, sodium hydride, or potassium t-butoxide in apolar aprotic solvent such as DMF or DMSO with introduction of a sidechain bearing an appropriate leaving group such as a halide, or asulfonate group. Reduction of the nitro group in formula (XIII) could beaccomplished using iron in acetic acid or hydrogen gas in the presenceof a suitable palladium, platinum or nickel catalyst. Conversion ofcompounds of formula (XIV) to the imidazoline of formula (XV) is bestaccomplished using ethylenediamine in the presence of a catalyst such aselemental sulfur with heating. The cyclization of compounds of formula(XV) to those of formula (XVI) is accomplished using cyanogen bromide inthe presence of an amine base such as triethylamine,diisopropylethylamine, or pyridine in a halogenated solvent such as DCMor dichloroethane. Lastly, amides of formula (I) can be formed usingactivated esters such as acid chlorides and anhydrides or alternativelyformed using carboxylic acids and appropriate coupling agents such asPYBOP, DCC, or EDCI in polar aprotic solvents.

In Reaction Scheme 3, a compound of formula (X), prepared as describedabove, can be converted to amide (XVI) using activated esters such asacid chlorides and anhydrides or alternatively formed using carboxylicacids and appropriate coupling agents such as PYBOP, DCC, or EDCI inpolar aprotic solvents. This could then be converted to compounds offormula (I) using a base such as cesium carbonate, sodium hydride, orpotassium t-butoxide in a polar aprotic solvent such as DMF or DMSO withintroduction of a side chain bearing an appropriate leaving group suchas a halide, or a sulfonate group.

In Reaction Scheme 4, a compound of formula (IX), prepared as describedabove, can be converted to amide (XVII) using activated esters such asacid chlorides and anhydrides or alternatively formed using carboxylicacids and appropriate coupling agents such as PYBOP, DCC, or EDCI inpolar aprotic solvents. Removal of the protecting group in formula(XVII) will be dependent on the group selected and can be accomplishedby standard methods (Greene, T. W.; Wuts, P. G. M.; Protective Groups inOrganic Synthesis; Wiley & Sons: New York, 1999). Alkylation of thephenol in formula (XVI) can be achieved using a base such as cesiumcarbonate, sodium hydride, or potassium t-butoxide in a polar aproticsolvent such as DMF or DMSO with introduction of a side chain bearing anappropriate leaving group such as a halide, or a sulfonate group.

In Reaction Scheme 5, a compound of formula XVIII can be converted tothe bis chloride compound of formula XIX using chlorinating agents suchas POCl₃ or COCl₂ in aprotic solvents. The chloride thus obtained can beconverted to imidazolines of formula XXI through reaction withappropriate quantities of ethanolamine or a suitably protectedsubstitute, followed by activation with a suitable activating agent suchas a sulfonyl chloride, PPh₃, or an halogenating agent such as SOCl₂.Chloride XXI can be converted to amine XXII through the use of anysource of nucleophilic amine such as ammonia, phthalimide, or protectedamines such as benzyl amine in a polar solvent such as DMF or DMSO.Formation of the phenol depicted in formula X can be accomplishedthrough deprotection of the methyl ether using any of the conditionsoutlined in the literature (Greene, T. W.; Wuts, P. G. M.; ProtectiveGroups in Organic Synthesis; Wiley & Sons: New York, 1999).

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their entirety.

INTERMEDIATES Intermediate A Preparation of pyrimidine 4-carboxylic acid

4-Methylpyrimidine (1.00 g, 10.6 mmol) was diluted in water (90 mL).Potassium permanganate (4.20 g, 26.5 mmol) and potassium hydroxide (4.20g, 74.8 mmol) were added, and the mixture was heated at 75° C. for 1.5h. Ethanol was added dropwise, and the precipitate was removed byfiltration through Celite. The filtrate was concentrated under reducedpressure, diluted in water, and treated with a concentrated HCl solutionuntil acidic. The title compound precipitated as a fine powder, whichwas collected by vacuum filtration and dried in a vacuum oven (770 mg,58%): ¹H NMR (DMSO-d₆) δ: 13.92 (1H, br s), 9.35 (1H, d), 9.05 (1H, d),7.99 (1H, dd).

Intermediate B Preparation of 2-aminopyrimidine-5-carboxylic acid

Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate wasprepared as described by Zhichkin et al. (Synthesis 2002, 6, p. 7720).

Sodium (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (1.37g, 7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride(640 mg, 6.7 mmol) was added. The mixture was stirred at 100° C. for 1h, then was cooled to rt and diluted with water. Methyl2-aminopyrimidine-5-carboxylate precipitated as a light yellow solid,which was isolated by vacuum filtration (510 mg, 50%): ¹H NMR (DMSO-d₆)δ: 8.67 (s, 2H), 7.56 (br s, 2H), 3.79 (s, 3H).

Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted inmethanol (5 mL) containing a few drops of water. Lithium hydroxide (122mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60° C.overnight. The mixture was concentrated under reduced pressure, thendiluted in water and adjusted to pH 4 with 1 M HCl.2-Aminopyrimidine-5-carboxylic acid precipitated as a white solid, whichwas isolated by vacuum filtration (244 mg, 90%): ¹H NMR (DMSO-d₆) δ:12.73 (1H, br s), 8.63 (2H, s), 7.44 (2H, br s).

Intermediate C Preparation of 4-(3-chloropropyl)morpholine hydrochloride

To a solution of 1-bromo-3-chloropropane (45 g, 0.29 mol) in toluene(100 mL) was added morpholine (38 g, 0.44 mol). The solution was stirredat 84° C. for 3 h, during which time a precipitate formed. After coolingto rt, the precipitate was isolated by vacuum filtration, washed withether, and the solid was discarded. The mother liquor was acidified withHCl (4 M in dioxane, 72 mL, 0.29 mol), which caused the desired productto precipitate as an HCl salt. Solvent was removed under reducedpressure, and the resultant solid was dried to afford the title compound(53 g, 90%): ¹H NMR (DMSO-d₆) δ: 11.45 (1H, br s), 3.94-3.77 (4H, m),3.74 (2H, t), 3.39 (2H, m), 3.15 (2H, m), 3.03 (2H, m), 2.21 (2H, m).

Intermediate D Preparation of 2-amino-4-propylpyrimidine-5-carboxylicacid

To a solution of ethyl 2-amino-4-propyllpyrimidine-5-carboxylate (1.0 g,4.8 mmol) in MeOH (20 mL) and THF (30 mL) was added a 2 N NaOH solution(10 mL). The solution was stirred at room temperature overnight and thenneutralized with 1 N HCl (20 mL). It was then concentrated under reducedpressure to 30 mL, filtered, and dried to give the desired product whichwas used without further purification (0.6 g, 69%).

Intermediate E Preparation of 6-amino-2-methylnicotinic acid

A suspension of 6-amino-2-methylnicotinonitrile (1.0 g, 7.5 mmol) in anaqueous KOH solution (20%, 12 mL) was heated at the reflux temperaturefor 3 days. After this time, it was cooled to room temperature,neutralized with concentrated HCl, filtered and dried to give thedesired product which was used without further purification (1.1 g,96%).

Intermediate F Preparation of tert-butyl2-(2-hydroxyethyl)morpholine-4-carboxylate

Methyl morpholin-2-yl acetate (5.0 g, 31.4 mmol) was diluted with THF(10 mL) and water (10 mL) and treated with potassium carbonate (4.34 g,31.4 mmol). The thick suspension slowly went into solution.Di-tert-butyl dicarbonate (6.85 g, 31.4 mmol) was added and the reactionmixture was stirred at rt overnight. The reaction mixture was thenextracted with THF and EtOAc. The organic layer was dried (MgSO₄) andconcentrated under reduced pressure. The sticky oil was triturated withether and the resulting solid was collected by vacuum filtration (3.7 g,45%). The mixture was diluted in THF (20 mL) and treated with a solutionof sodium hydroxide (2 N, 5 mL) and stirred overnight. The reactionmixture was concentrated under reduced pressure and then diluted withwater and EtOAc. The pH of the aqueous layer was adjusted to 5, and theorganic layer was separated, dried (MgSO₄) and concentrated underreduced pressure. The solid (2 g, 8.15 mmol) was then dissolved in THF(10 mL) and treated with a borane solution (1 M in THF, 16 mL, 16.4mmol) and the mixture stirred at rt for 12 h. The reaction mixture wasthen diluted with methanol (100 mL) and stirred at rt overnight. Thesolution was then concentrated under reduced pressure and then dilutedwith DCM. The solution was filtered through a layer of silica to removethe borane salts, and the filtrate was concentrated under reducedpressure to give an oil (1.8 g, 96%): HPLC MS RT=2.22 min, MH⁺=232.2; ¹HNMR (DMSO-d₆) δ: 4.46 (1H, t), 3.81-3.73 (2H, m), 3.72-3.64 (1H, br d),3.45 (2H, t), 3.40-3.29 (3H, m), 2.93-2.73 (1H, br s), 1.55-1.48 (2H,m), 1.39 (9H, s).

Intermediate G Preparation of2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-chloropropyl)morpholine

Step 1: Preparation of Morpholin-2-ylmethanol trifluoroacetate

A solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1.1g, 5.06 mmol) in DCM (15 mL) was treated with trifluoroacetic acid (2.5mL, 10.1 mmol) and stirred at rt overnight. The reaction mixture wasconcentrated under reduced pressure to yield a thick oil (1.1 g, 94%):NMR (DMSO-d₆) δ: 9.30 (1H, s), 4.95 (1H, s), 4.19-4.06 (1H, br s), 3.93(1H, dd), 3.76-3.63 (2H, m), 3.47-3.32 (2H, m), 3.22-3.09 (3H, m), 3.92(1H, td), 2.76 (1H, t).

Step 2: Preparation of2-(f{[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine

Morpholin-2-ylmethanol trifluoroacetate (0.7 g, 3.03 mmol) in DCM wastreated with triethylamine (1.67 mL, 12.1 mmol) andtert-butyldimethylsilyl chloride (0.91 g, 6.06 mmol). The mixture wasstirred at rt for 2 h and then filtered. The filtrate was thenconcentrated under reduced pressure and the residue was suspended in adilute solution of sodium hydroxide (10%, 5 mL), and the mixture wasstirred for 30 min. The mixture was then extracted with DCM andconcentrated under reduced pressure to a foam. The product was taken tothe next step without further purification: ¹H NMR (DMSO-d₆) δ:5.40-5.14 (1H, br s), 3.69 (1H, m), 3.56-3.50 (1H, m), 3.46-3.3 (3H, m),3.27-2.97 (1H, br s), 2.78 (1H, dd), 2.68-2.55 (2H, m), 2.35 (1H, m),0.87-0.82 (9H, m), 0.02 (6H, s).

Step 3: Preparation of2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-chloropropyl)morpholine

A solution of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine (2.1g, 9.07 mmol) in DCM (20 mL) was treated with triethylamine (3.8 mL,27.2 mmol) and 1-chloro-3-iodopropane (1.95 mL, 18.1 mmol). The reactionmixture was stirred at rt overnight. The reaction mixture wasconcentrated under reduced pressure then purified by MPLC (ISCO, 0%MeOH/100% DCM to 25% MeOH/75% DCM). The product was isolated as an oil(560 mg, 20%): HPLC MS RT=2.66 min, MH⁺=308.4, 310.4; ¹H NMR (DMSO-d₆)δ: 3.79-3.69 (1H, m), 3.63 (2H, t) 3.59-3.52 (1H, m), 3.50-3.36 (3H, m),2.73 (1H, d), 2.61 (1H, d), 2.35 (2H, t), 1.94 (1H, td), 1.83 (2H, qt),1.73 (1H, t), 0.83 (9H, s), 0.00 (6H, s).

Intermediate H Preparation of4-[(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride

3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM(15 mL) and cooled to 0° C. The cooled solution was treated with thionylchloride (1.81 mL, 24.8 mmol) and then heated at the reflux temperaturefor 1 h. The reaction mixture was then concentrated under reducedpressure to give a solid (2.5 g, 97%): ¹H NMR (DMSO-d₆) δ: 11.4 (1H, brs), 5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m),3.55-3.33 (4H, m), 3.26-3.06 (2H, br s).

Intermediate I Preparation of 6-(cyclopentylamino)nicotinic acid

6-Fluoronicotinic acid (300 mg, 2.13 mmol) and cyclopentylamine (0.84mL, 8.50 mmol) were combined in anhydrous THF (5 mL) and triethylamine(0.59 mL, 4.25 mmol). The mixture was heated at 60° C. for 3 days. Themixture was concentrated under reduced pressure, and the residue wassuspended in water. The aqueous mixture was brought to pH 3 withphosphoric acid. The resulting precipitate was collected by vacuumfiltration, washed with water, and dried in a vacuum oven for 1 h at 50°C. to give the title compound as a solid (63 mg, 14%): HPLC MS RT=1.14min, MH⁺=207.2; ¹H NMR (DMSO-d₆) δ: 12.29 (1H, broad s), 8.50 (1H, d),7.73 (1H, dd), 7.29 (1H, d), 6.42 (1H, d), 4.16 (1H, broad s), 1.90 (2H,m), 1.67 (2H, m), 1.53 (2H, m), 1.43 (2H, m).

EXAMPLES Example 1 Preparation ofN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide

Step 1: Preparation of 4-formyl-2-methoxy-3-nitrophenyl acetate

Fuming nitric acid (2200 mL) under nitrogen was cooled to 0° C. at whichtime vanillin acetate (528 g, 2.7 mol) was added portionwise, keepingthe internal temperature below 10° C. After 2 h the resulting mixturewas poured over ice with stirring. The slurry was filtered and theresulting solids were washed with water (3×100 mL) and air-dried. After2 days the solids were heated in DCM (3000 mL) until completedissolution. The solution was allowed to cool to room temperature whilehexanes (3000 mL) was added dropwise. The solids were filtered, washedwith hexanes (500 mL) and air dried to give the desired product (269 g,41%): ¹H NMR, (DMSO-d₆) δ: 9.90 (s, 1H), 7.94 (d, 1H), 7.75 (d, 1H),3.87 (s, 3H), 2.40 (s, 3H).

Step 2: Preparation of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde

A mixture of 4-formyl-2-methoxy-3-nitrophenyl acetate 438 g (1.8 mol)and potassium carbonate (506 g, 3.7 mol) in MeOH (4000 mL) was stirredat room temperature for 16 h. The reaction mixture was concentratedunder reduced pressure to afford a viscous oil. This was dissolved inwater, acidified using a solution of HCl (2 N) and extracted with EtOAc.The organic layer was washed with brine, dried (MgSO₄) and filtered. Thesolvent was concentrated under reduced pressure to ⅓ volume and theresulting solids were filtered and air-dried to give the title compound(317 g, 88%): ¹H NMR (DMSO-d₆) δ: 9.69 (1H, s), 7.68 (1H, d), 7.19 (1H,d), 3.82 (3H, s).

Step 3: Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde

4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (155 g, 786 mmol) was dissolvedin DMF (1500 mL) and the stirred solution was treated with potassiumcarbonate (217 g, 1.57 mol) followed by benzyl bromide (161 g, 0.94mol). After stirring for 16 h the reaction mixture was concentratedunder reduced pressure and separated between water (2 L) and EtOAc (2L). The organic layer was washed with brine (3×2 L), dried (sodiumsulfate) and concentrated under reduced pressure. The resulting solidswere triturated with Et₂O (1 L) to give the title compound (220 g, 97%):¹H NMR (DMSO-d₆) δ: 9.77 (1H, s), 7.87 (1H, d), 7.58 (1H, d), 7.51 (1H,m), 7.49 (1H, m), 7.39 (3H, m), 5.36 (2H, s), 3.05 (3H, s).

Step 4: Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile

Iodine (272 g, 1.1 mmol) was added to a mixture of4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (220 g, 766 mmol) andammonium hydroxide (28% solution, 3 L) dissolved in THF (5 L). After 16h the reaction mixture was treated with sodium sulfite (49 g, 383 mmol)and concentrated under reduced pressure to afford a thick slurry. Theslurry was filtered, washed with water (250 mL) and dried to afford thetitle compound as a solid (206 g, 95%): ¹H NMR (DMSO-d₆) δ: 7.89 (1H,d), 7.59 (1H, d), 7.49 (2H, m), 7.40 (3H, m), 5.35 (2H, s), 3.91 (3H,s).

Step 5: Preparation of 2-amino-4-(benzyloxy)-3-methoxybenzonitrile

A degassed solution of 4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile (185g, 651 mmol) in glacial acetic acid (3500 mL) and water (10 mL) wascooled to 5° C. and treated with iron powder (182 g, 3.25 mol). After 3days the reaction mixture was filtered through Celite, and the filtrateconcentrated under reduced pressure. The oil, thus obtained, was treatedwith brine, neutralized with a sodium bicarbonate solution and extractedinto DCM. The resulting emulsion was filtered through Celite after whichthe organic layer was separated, washed with brine, dried (sodiumsulfate) and concentrated under reduced pressure to afford the titlecompound as a solid (145 g, 88%): ¹H NMR (DMSO-d₆) δ: 7.32-7.44 (5H, m),7.15 (1H, d), 6.47 (1H, d), 5.69 (2H, s), 5.15 (2H, s), 3.68 (3H, s).

Step 6: Preparation of3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline

A mixture of 2-amino-4-(benzyloxy)-3-methoxybenzonitrile (144 g, 566mmol) and sulfur (55 g, 1.7 mol) in ethylenediamine (800 mL) wasdegassed for 30 minutes then heated to 100° C. After 16 h the reactionmixture was cooled to room temperature and then filtered. The filtratewas concentrated under reduced pressure, diluted with a saturated sodiumbicarbonate solution and extracted with EtOAc. The organic layer waswashed with brine, dried (sodium sulfate), filtered and concentratedunder reduced pressure.

The resulting solids were recrystallized from EtOAc and hexanes toafford the title compound (145 g, 86%): ¹H NMR (DMSO-d₆) δ: 7.27-7.48(5H, m), 7.14 (1H, d), 6.92 (2H, m), 6.64 (1H, m), 6.32 (1H, d), 5.11(2H, s), 3.67 (3H, s), 3.33 (2H, s).

Step 7: Preparation of8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

A mixture of3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (100 g,336 mmol) and triethylamine (188 mL) in DCM (3 L) was cooled to 0° C.and treated with cyanogen bromide (78.4 g, 740 mmol). The reactionmixture was stirred and allowed to warm to room temperature gradually.After 16 h the reaction mixture was diluted with a solution of saturatedsodium bicarbonate and extracted with DCM. The organic layer was washed3 times with saturated bicarbonate solution followed by multiple washeswith brine. The organic layer was dried (sodium sulfate) andconcentrated under reduced pressure to give a semi solid (130 g withtriethylamine salt contamination): ¹H NMR (DMSO-d₆) δ: 7.30-7.48 (7H,m), 5.31 (2H, s), 4.32 (2H, m), 4.13 (2H, m), 3.81 (3H, s).

Step 8: Preparation of5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-olbis(trifluoroacetate)

3-(Benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (30 g,93 mmol) was added portionwise over 1 h to a round bottom flaskcontaining TFA (400 mL) precooled with an ice bath. The reaction mixturewas heated to 60° C. and allowed to stir at this temperature for 17 h atwhich time it was cooled to rt and the reaction mixture concentratedunder reduced pressure. The resulting residue was taken up in DCM andhexanes and concentrated under reduced pressure. The material thusobtained was dissolved in MeOH and DCM (250 mL, 1:1) and concentratedunder reduced pressure. The resulting solid was dried overnight undervacuum with low heat to give the title compound (44.7 g, >100%): ¹H NMR(DMSO-d₆) δ: 7.61 (1H, m), 6.87 (1H, m), 4.15 (2H, br t), 4.00 (2H, m),3.64 (3H, s).

Step 9: Preparation of7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

5-Amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-olbis(trifluoroacetate) (500 mg, 1.1 mmol) was diluted in DCM (10 mL), andtriethylamine (0.75 mL, 5.4 mmol) was added. The suspension was stirredat rt for 1.5 h, after which time5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-oltrifluoroacetate was isolated. The compound, thus prepared, (1.1 mmol)was dissolved in DMF (10 mL). Cesium carbonate (1.41 g, 4.3 mmol) andIntermediate C (218 mg, 1.1 mmol) were added, and the mixture wasstirred at 70° C. for 30 min. Additional Intermediate C (109 mg, 0.55mmol) and cesium carbonate (350 mg, 1.1 mmol) were added, and stirringwas continued for 1 h. Another aliquot of Intermediate C (109 mg, 0.55mmol) was added, and the temperature was increased to 75° C. After 3 h,the reaction mixture was cooled to rt and filtered through a pad ofCelite, washing with methanol and DCM. The filtrate was concentratedunder reduced pressure, dry loaded onto silica gel, and purified bybiotage eluting with 5-10% methanol in DCM followed by 5-15% methanolicammonia (2.0 M, Aldrich) in DCM. The resultant oil was triturated with a1:1 mixture of hexanes:EtOAc (15 mL) to afford the desired as a solid(171 mg, 44%): HPLC MS RT=1.07 min, MH⁺=360.3; ¹H NMR (DMSO-d₆) δ: 7.43(1H, d), 6.73 (3H, m), 4.03 (2H, t), 3.88 (4H, m), 3.69 (3H, s), 3.55(4H, m), 2.42 (2H, t), 2.35 (4H, m), 1.87 (2H, m).

Step 10: Preparation ofN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(100 mg, 0.22 mol) was dissolved in DMF (5 mL), andpyrimidine-5-carboxylic acid (41 mg, 0.33 mmol) was added. PYBOP (173mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 0.89 mmol) weresubsequently added, and the mixture was stirred at rt overnight. EtOAcwas added, and the precipitate was isolated by vacuum filtration to givethe title compound (12 mg, 11%): HPLC MS RT=1.07 min, MH⁺=466.2; ¹H NMR(DMSO-d₆+2 drops TFA-d) δ: 9.48 (2H, s), 9.39 (1H, s), 8.05 (1H, d),7.47 (1H, d), 4.59 (2H, m), 4.35 (2H, br t), 4.26 (2H, m), 4.02 (3H, s),4.00 (2H, m), 3.67 (2H, br t), 3.52 (2H, m), 3.33 (2H, m), 3.16 (2H, m),2.27 (2H, m).

Example 2 Preparation ofN-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

8-{3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(200 mg, 0.52 mmol) was dissolved in DMF (2.0 mL), and nicotinic acid(76 mg, 0.62 mmol) was added. PYBOP (322 mg, 0.62 mmol) anddiisopropylethylamine (0.33 mL, 1.55 mmol) were subsequently added, andthe mixture was stirred at room temperature overnight. EtOAc was added,and the precipitate was isolated by vacuum filtration to give the titlecompound (156 mg, 61%): HPLC MS RT=1.34 min, MH⁺=493.3; ¹H NMR(DMSO-d₆+2 drops TFA-d) δ: 9.53 (1H, s), 9.03 (1H, d), 9.00 (1H, d),8.07 (1H, d), 8.01 (1H, dd), 7.49 (1H, d), 4.58 (2H, m), 4.34 (2H, t),4.27 (2H, m), 4.03 (3H, s), 3.81 (2H, m), 3.53 (2H, d), 3.29 (2H, m),2.69 (2H, m), 2.27 (2H, m), 1.15 (6H, d).

Example 3 Preparation ofN-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide

8-{3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(120 mg, 0.31 mmol) was dissolved in DMF (1.5 mL), and2,4-dimethyl-1,3-thiazole-5-carboxylic acid (58 mg, 0.37 mmol) wasadded. PYBOP (193 mg, 0.37 mmol) and diisopropylethylamine (0.16 mL,0.93 mmol) were subsequently added, and the mixture was stirred at roomtemperature overnight. EtOAc was added, and the precipitate was isolatedby vacuum filtration to give the title compound (131 mg, 80%): HPLC MSRT=2.05 min, MH⁺=527.1; ¹H NMR (DMSO-d₆+2 drops TFA-d) δ: 8.02 (1H, d),7.43 (1H, d), 4.38 (2H, m), 4.32 (2H, m), 4.22 (2H, m), 4.00 (3H, s),3.81 (2H, m), 3.53 (2H, d), 3.28 (2H, m), 2.72-2.63 (8H, m), 2.26 (2H,m), 1.13 (6H, d).

Example 4 Preparation of2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(250 mg, 0.70 mol) was dissolved in DMF (4 mL), and2-amino-1,3-thiazole-5-carboxylic acid (110 mg, 0.76 mmol) was added.PYBOP (543 mg, 1.04 mmol) and diisopropylethylamine (0.61 mL, 3.50 mmol)were subsequently added, and the mixture was stirred at room temperatureovernight. The desired product was isolated via HPLC to give the titlecompound (80.0 mg, 24%): HPLC MS RT=1.03 min, MH⁺=486.3; ¹H NMR(MeOH-d₄+2 drops TFA-d) δ: 7.90 (1H, d), 7.79 (1H, d), 7.50-7.60 (2H,m), 3.70 (2H, m), 3.30 (2H, d), 3.20 (2H, q), 2.10 (2H, s), 1.35 (10H,m).

Example 5 Preparation of2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(100 mg, 0.28 mol) was dissolved in DMF (3 mL), and2-aminopyridine-4-carboxylic acid (38 mg, 0.28 mmol) was added. PYBOP(217 mg, 0.42 mmol) and diisopropylethylamine (0.15 mL, 0.83 mmol) weresubsequently added, and the mixture was stirred at rt overnight. Themixture was purified by HPLC to give the title compound (50 mg, 37%). LCMS RT=1.02 min, MH⁺=480.3. ¹H NMR (DMSO-d₆) δ: 13.25 (1H, br s), 10.15(1H, br s), 8.42 (1H, br s), 8.08 (1H, s), 8.06 (1H, d), 7.43 (1H, d),7.75 (1H, s), 7.50 (1H, d), 7.38 (1H, dd), 4.50 (2H, dd), 4.35 (2H, brt), 4.27 (2H, dd), 4.01 (3H, s), 3.99 (2H, br s), 3.66 (2H, t), 3.50(2H, d), 3.31 (2H, br t), 3.13 (2H, m), 2.25 (2H, m).

Example 6 Preparation of2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(100 mg, 0.28 mol) was dissolved in DMF (3 mL), and2-amino-4-methylthiazole-5-carboxylic acid (44 mg, 0.28 mmol) was added.PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (0.15 mL, 0.83 mmol)were subsequently added, and the mixture was stirred at rt overnight.The mixture was purified by HPLC to give the title compound (6 mg, 4%):LC MS RT=1.06 min, MH⁺=500.1; ¹H NMR (DMSO-d₆) δ: 12.59 (1H, s), 7.55(1H, d), 7.47 (1H, s), 6.98 (1H, d), 4.13 (2H, t), 3.93 (4H, m), 3.86(3H, s), 3.55 (4H, t), 2.47 (3H, s), 2.45 (2H, t), 2.33 (4H, m), 1.93(2H, m).

Example 72-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(100 mg, 0.28 mol) was dissolved in DMF (3 mL), and Intermediate D (50mg, 0.28 mmol) was added. PYBOP (217 mg, 0.42 mmol) anddiisopropylethylamine (0.15 mL, 0.83 mmol) were subsequently added, andthe mixture was stirred at rt overnight. The resulting precipitate wasfiltered and washed with MeOH to give the title compound (76 mg, 52%):LC MS RT=1.64 min, MH⁺=523.3; ¹H NMR (DMSO-d₆ with 2 drops TFA-d) δ:10.04 (1H, br s), 9.14 (1H, s), 8.02 (1H, d), 7.43 (1H, d), 4.48 (2H,dd), 4.33 (2H, t), 4.21 (2H, dd), 4.01 (2H, m) 3.98 (3H, s), 3.65 (2H,t), 3.52 (2H, d), 3.30 (2H, br t), 3.13 (4H, m), 2.24 (2H, m), 1.68 (2H,m), 0.95 (3H, t).

Example 8 Preparation ofN-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide

Step 1: Preparation ofN-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (21g, 65 mmol) and nicotinic acid (12 g, 97.7 mmol) were suspended in DMF(240 mL). Diisopropylethylamine (33.7 g, 260.4 mmol) and then PYBOP (51g, 97.7 mmol) were added and the resulting mixture stirred with overheadstirring for 3 days at ambient temperature. At this time, the resultantprecipitate was isolated by vacuum filtration. After repeated washingwith EtOAc, the material was dried under vacuum with slight heating toyield the title compound (27.3 g, 98%): HPLC MS RT=1.09 min, MH⁺=481.2;¹H NMR (DMSO-d₆+2 drops TFA-d) δ: 9.32 (1H, s), 8.89 (1H, br m), 8.84(1H, d), 7.89 (1H, br m), 7.82 (1H, d), 7.37 (1H, d), 7.27 (1H, d), 7.16(6H, m), 5.18 (2H, s), 4.36 (2H, t), 4.04 (2H, t), 3.78 (3H, s).

Step 2: Preparation ofN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

N-[8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide(20 g, 45.1 mmol) was added portionwise over 1 h to a round bottom flaskcontaining TFA (400 mL) precooled with an ice bath. The reaction mixturewas heated to 60° C. and allowed to stir at this temperature for 17 h atwhich time it was cooled to ambient. The reaction mixture was thenconcentrated under reduced pressure. The resulting residue was taken upin DCM and hexane and concentrated under reduced pressure. The materialthus obtained was dissolved in MeOH and DCM (250 mL, 1:1) andconcentrated under reduced pressure. The resulting solids were driedovernight under vacuum with low heat to give the title compound (17.3 g,66%): HPLC MS RT=1.09 min, MH⁺=481.2; ¹H NMR (DMSO-d₆+2 drops TFA-d) δ:13.41 (1H, s), 12.21 (1H, br s), 9.38 (1H, s), 8.78 (1H, d), 8.53 (1H,d), 7.85 (1H, d), 7.59 (1H, m), 7.17 (1H, d), 4.54 (2H, m), 4.21 (2H,m), 3.98 (3H, s).

Step 3: Preparation of tert-Butyl2-[2-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)ethyl]morpholine-4-carboxylate

A solution of Intermediate F (420 mg, 1.83 mmol) in DMF (5 mL) wastreated with triethylamine (340 μL, 2.44 mmol) and methanesulfonylchloride (141 μL, 1.83 mmol) and the mixture was stirred at rt for 1.5h. A suspension of the compound prepared in example 8 step 2 (650 mg,1.22 mmol) in DMF (20 mL) was treated with cesium carbonate (2.0 g, 6.10mmol) and stirred for 1.5 h before adding the preformed and filteredmesylate. The reaction mixture was stirred at 60° C. overnight and thenconcentrated under reduced pressure and the residue was extracted with asolution of 20% isopropanol/80% chloroform and washed with a saturatedsolution of sodium hydrogen carbonate. The organics were dried (MgSO₄)and concentrated under reduced pressure. The residue was triturated withEtOAc and filtered to give the title compound as a solid (850 mg, 84%):HPLC MS RT=2.48 min, MH⁺=551.2; ¹H NMR (DMSO-d₆) δ: 12.7 (1H, s), 9.32(1H, dd), 8.72 (1H, dd), 8.46 (1H, dt), 7.60 (1H, d), 7.51 (1H, dd),7.07 (1H, d), 4.23-4.19 (2H, m), 4.15-4.10 (2H, m), 4.04-4.02 (2H, m),3.93 (3H, s), 3.91-3.78 (2H, m), 3.75-3.66 (1H, m) 3.56-3.48 (1H, m),3.41-3.35 (1H, td), 2.97-2.76 (1H, br s), 2.74-2.55 (1H, br s),2.04-1.94 (1H, br m) 1.94-1.84 (1H, br m), 1.39 (9H, s).

Step 4: Preparation ofN-[7-methoxy-8-(2-morpholin-2-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide.

tert-Butyl2-[2-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)ethyl]morpholine-4-carboxylate(650 mg, 1.44 mmol) was dissolved in trifluoroacetic acid (10 mL) andstirred at rt for 4 h. The reaction mixture was concentrated underreduced pressure, and the resulting oil was diluted with methanol (1 mL)and pulled through a silica bound-NH₂ cartridge. The solution wasconcentrated under reduced pressure to give the title compound as asolid (45 mg, 69%): HPLC MS RT=0.21 min, MH⁺=451.1; ¹H NMR (DMSO-d₆) δ:12.8-12.7 (1H, br s), 9.32 (1H, s), 8.73 (1H, d), 8.46 (1H, d), 7.60(1H, d), 7.54-7.49 (1H, m), 7.06 (1H, d) 4.22-3.99 (6H, m), 3.94 (3H,s), 3.78 (1H, d), 3.66-3.58 (1H, m), 3.47 (1H, t), 2.95 (1H, d),2.82-2.65 (2H, m), 1.98-1.78 (2H, m).

Step 5: Preparation ofN-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide

N-[7-Methoxy-8-(2-morpholin-2-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidetrifluoroacetate (100 mg, 0.18 mol) in THF was treated with acetaldehyde(30 μL, 0.53 mmol) and stirred for 30 min. before adding sodiumtriacetoxyborohydride (113 mg, 0.53 mmol) and acetic acid (13 μL, 0.23mmol). The reaction mixture was stirred at 60 C overnight after which itwas diluted with methanol and a drop of 2 N hydrochloric acid todissolve all solids. The crude solution was purified by HPLC (Gilson, 5%MeCN/95% H₂O to 50% MeCN/50% H₂O gradient, 0.1% TFA). The fractions wereconcentrated under reduced pressure then diluted with a minimum ofmethanol and pulled through a silica bound NH₂ cartridge to give thetitle compound as a solid (17 mg, 20%): HPLC MS RT=0.21 min, MH⁺=479.1;¹H NMR (DMSO-d₆) δ: 12.75 (1H, s), 9.32 (1H, s), 8.71 (1H, d), 8.45 (1H,d), 7.59 (1H, d), 7.54-7.47 (1H, m), 7.06 (2H, d), 4.23-4.08 (3H, m),4.06-3.98 (2H, m) 3.92 (3H, s), 3.77 (1H, d), 3.67-3.57 (1H, m), 3.46(1H, t), 2.84 (1H, d), 2.68 (1H, d), 2.30 (2H, q), 1.99-1.79 (3H, m),1.74 (1H, t), 0.99 (3H, t).

Example 9 Preparation ofN-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide

Sodium hydride (865 mg, 22 mmol, 60% dispersion in mineral oil) wasdiluted in DMF (35 mL).N-(8-Hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamidebis(trifluoroacetate) (1.75 g, 3.1 mmol) was added, followed by2-chloro-N,N-dimethylethanamine hydrochloride (890 mg, 6.2 mmol). Thereaction mixture was stirred at rt until gas evolution ceased and thenwas heated to 50° C. for 2 h. At this time, the mixture was cooled tort, and an additional equivalent of 2-chloro-N,N-dimethylethanaminehydrochloride (445 mg, 3.1 mmol) was added. The resulting reactionmixture was stirred at 50° C. overnight. After cooling to rt, the excesssodium hydride was carefully quenched by the addition of water and themixture was extracted several times with DCM. The combined organiclayers were dried (sodium sulfate) and concentrated under reducedpressure. The resultant solid was triturated with EtOAc and hexanes toafford the title compound as a solid (710 mg, 56%): HPLC MS RT=1.09 min,MH⁺=410.1; ¹H NMR (DMSO-d₆+2 drops TFA-d) δ: 9.47 (2H, s), 9.39 (1H, s),8.12 (1H, d), 7.52 (1H, d), 4.61 (4H, m), 4.26 (2H, m), 4.03 (3H, s),3.67 (2H, br t), 2.93 (6H, s).

Example 10 Preparation ofN-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

Step 1: Preparation ofN-(8-{3-[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

A suspension ofN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamidebis-trifluoroacetate (650 mg, 1.22 mmol) in DMF (20 mL) was treated withcesium carbonate (2.0 g, 6.10 mmol) and stirred for 1.5 h before addingIntermediate G (0.56 g, 1.83 mmol) and triethylamine (0.34 mL, 2.44mmol). The reaction mixture was stirred at 60° C. overnight, after whichtime it was concentrated under reduced pressure and the residue wasextracted with a solution of 20% isopropanol/80% chloroform and washedwith a saturated solution of sodium hydrogen carbonate. The organiclayer was dried (MgSO₄) and concentrated under reduced pressure. Theresidue was triturated with EtOAc and filtered to give the titlecompound as a solid (260 mg, 35%): HPLC MS RT=2.36 min, MH⁺=609.2; ¹HNMR (CD3OD-d₄) δ: 9.24 (1H, d), 8.60 (1H, dd), 8.48 (1H, dt), 7.53 (1H,d), 7.46 (1H, dd), 6.94 (1H, d), 4.21-4.05 (6H, m), 3.88 (1H, br d),3.74-3.55 (4H, m), 2.95 (1H, d), 2.82 (1H, d), 2.60 (2H, t) 2.22-2.13(1H, m), 2.05 (2H, qt), 1.94 (1H, t), 0.91 (9H, s), 0.08 (6H, s).

Step 2: Preparation ofN-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

N-(8-{3-[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide(260 mg, 0.43 mmol) was suspended in THF (2 mL) and treated with asolution of tetra-n-butylammonium fluoride (1N, 0.64 mL, 0.64 mmol) inTHF. The resulting mixture was stirred at rt for 4 h and was thendiluted with water and extracted with 20% isopropanol/80% chloroform,dried (MgSO₄) and concentrated under reduced pressure. The residue wasthen triturated with methanol and filtered to give the product as asolid (100 mg, 47%): HPLC MS RT=0.19 min, MH⁺=495.2; ¹H NMR (DMSO-d₆) δ:12.7 (1H, s), 9.33 (1H, dd), 8.73 (1H, dd), 8.46 (1H, dt), 7.60 (1H, d),7.54-7.49 (1H, m), 7.06 (1H, d) 4.66 (1H, t), 4.20-4.09 (4H, m),4.07-3.98 (2H, m) 3.93 (3H, s), 3.76 (1H, br d), 3.48 (1H, td),3.42-3.26 (4H, m), 2.83 (1H, d), 2.70 (1H, d), 2.47 (2H, t), 2.03-1.91(3H, m).

Example 11 Preparation ofN-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

Cesium carbonate (3 g, 9.37 mmol) was added to a suspension ofN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamidebis-trifluoroacetate (1.0 g, 1.88 mmol) in DMF (40 mL) and stirred for1.5 h before adding Intermediate H (0.39 g, 1.88 mmol). After 3 h, thereaction mixture was treated with another equivalent of Intermediate Hand stirred at 60° C. overnight. The reaction mixture was concentratedunder reduced pressure and the product was extracted with a solution of20% isopropanol/80% chloroform and washed with a saturated solution ofsodium hydrogen carbonate. The organics were dried (MgSO₄) andconcentrated under reduced pressure, and the resulting residue wastriturated with EtOAc and filtered. The solid was then purified by HPLC(Gilson, 5% MeOH/95% H₂O to 50% MeOH/50% H₂O gradient, 0.1% NH₄OH) togive the title compound (160 mg, 18%): HPLC MS RT=0.19 min, MH⁺=495.2;¹H NMR (DMSO-d₆+1 drop TFA-d) δ: 13.40-13.38 (1H, br s), 9.45 (1H, d),8.90 (1H, dd), 8.72 (1H, d), 8.06 (1H, d), 7.77 (1H, dd), 7.51 (1H, d)4.59 (2H, t), 4.49-4.41 (1H, br s), 4.33-4.22 (4H, m), 4.06 (3H, s)4.05-3.92 (2H, m), 3.86-3.67 (2H, m), 3.51 (2H, d), 3.43-3.13 (4H, m).

Example 12 Preparation ofN-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide1-oxide

Step 1: Preparation ofN-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide1-oxide

The title compound was synthesized from8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine asdescribed in Example 8, step 1 (1.31 g, 95%): HPLC MS RT=2.38 min,MH⁺=444.1; ¹H NMR (DMSO-d₆+2 drops TFA-d) δ: 4.00 (3H, s), 4.22-4.28(2H, m), 4.53-4.60 (2H, m), 5.42 (2H, s), 7.36-7.46 (3H, m), 7.51-7.54(2H, m), 7.58-7.69 (2H, m), 8.04 (1H, d), 8.17 (1H, d), 8.56 (1H, d),8.93-8.94 (1H, m).

Step 2: Preparation ofN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide1-oxide bistrifluoroacetate salt

The title compound was synthesized fromN-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide1-oxide as described in Example 8, step 2 (1.41 g, 94%): HPLC MS RT=0.35min, MH⁺=354.2; ¹H NMR (DMSO-d₆+2 drops TFA-d) δ: 3.97 (3H, s),4.17-4.24 (2H, m), 4.51-4.57 (2H, m), 7.17 (1H, d), 7.66 (1H, dd), 7.88(1H, d), 8.17 (1H, d), 8.53-8.56 (1H, m), 8.93-8.94 (1H, m).

Step 3: Preparation ofN-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide1-oxide

The title compound was synthesized fromN-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide1-oxide bistrifluoroacetate salt as described in Example 9 (42 mg, 37%):HPLC MS RT=1.08 min, MH⁺=439.2; ¹H NMR (DMSO-d₆+2 drops TFA-d) δ:2.19-2.25 (2H, m), 2.84 (3H, s), 3.23-3.28 (2H, m), 4.02 (3H, s),4.22-4.35 (4H, m), 4.54-4.61 (2H, m), 7.48 (1H, d), 7.66-7.71 (1H, m),8.06 (1H, d), 8.19 (1H, d), 8.57 (1H, d), 8.95 (1H, bs).

Example 13 Preparation of2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide

Step 1: Preparation of 4-hydroxy-3-methoxy-2-nitrobenzonitrile

4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (200 g, 1.01 mol) was dissolvedin THF (2.5 L) and then ammonium hydroxide (2.5 L) was added followed byiodine (464 g, 1.8 mol).

The resulting mixture was allowed to stir for 2 days at which time itwas concentrated under reduced pressure. The residue was acidified withHCl (2 N) and extracted into diethyl ether. The organic layer was washedwith brine and dried (sodium sulfate) and concentrated under reducedpressure. The residue was washed with diethyl ether and dried undervacuum to provide the title compound (166 g, 84%): ¹H NMR (DMSO-d₆) δ:11.91 (1H, s), 7.67 (1H, d), 7.20 (1H, d), 3.88 (3H, s)

Step 2: Preparation of3-methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile

To a solution of 4-hydroxy-3-methoxy-2-nitrobenzonitrile (3.9 g, 20.1mmol) in DMF (150 mL) was added cesium carbonate (19.6 g, 60.3 mmol) andIntermediate C (5.0 g, 24.8 mmol). The reaction mixture was heated at75° C. overnight then cooled to room temperature and filtered through apad of silica gel and concentrated under reduced pressure. The materialthus obtained was used without further purification

Step 3: Preparation of2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile

3-Methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile (7.7 g, 24.1mmol) was suspended in acetic acid (170 mL) and cooled to 0° C. Water(0.4 mL) was added, followed by iron powder (6.7 g, 120 mmol) and theresulting mixture was stirred at room temperature for 4 h at which timethe reaction mixture was filtered through a pad of Celite and washedwith acetic acid (400 mL). The filtrate was concentrated under reducedpressure to 100 mL and diluted with EtOAc (200 mL) at which timepotassium carbonate was added slowly. The resulting slurry was filteredthrough a pad of Celite washing with EtOAc and water. The layers wereseparated and the organic layer was washed with saturated sodiumbicarbonate solution. The organic layer was separated and passed througha pad of silica gel. The resultant solution was concentrated underreduced pressure to provide the title compound (6.5 g, 92%): ¹H NMR(DMSO-d₆) δ: 7.13 (1H, d), 6.38 (1H, d), 5.63 (2H, br s), 4.04 (2H, t),3.65 (3H, s), 3.55 (4H, br t), 2.41 (2H, t), 2.38 (4H, m), 1.88 (2H,quint.).

Step 4: Preparation of6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)aniline

To a degassed mixture of2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (6.5 g, 22.2mmol) and ethylene diamine (40 mL) was added sulfur (1.8 g, 55.4 mmol).The mixture was stirred at 100° C. for 3 h at which time water was addedto the reaction mixture. The precipitate that was formed was collectedand washed with water and then dried overnight under vacuum to providethe title compound (3.2 g, 43%): HPLC MS RT=1.25 min, MH⁺=335.2; ¹H NMR(DMSO-d₆) δ: 7.15 (1H, d), 6.86 (2H, br s), 6.25 (1H, d), 4.02 (2H, t),3.66 (3H, s), 3.57 (8H, m), 2.46 (2H, t), 2.44 (4H, m), 1.89 (2H,quint.).

Step 5: Preparation of7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

Cyanogen bromide (10.9 g, 102.9 mmol) was added to a mixture of6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)aniline(17.2 g, 51.4 mmol) and TEA (15.6 g, 154.3 mmol) in DCM (200 mL)precooled to 0° C. After 1 h the reaction mixture was concentrated underreduced pressure and the resulting residue stirred with EtOAc (300 mL)overnight at rt. The resulting slurry was filtered to generate the titlecompound contaminated with triethylamine hydrobromide (26.2 g, 71%):HPLC MS RT=0.17 min, MH⁺=360.2.

Step 6: Preparation of2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(100 mg, 0.22 mol) was dissolved in DMF (5 mL), and Intermediate B (46mg, 0.33 mmol) was added. PYBOP (173 mg, 0.33 mmol) anddiisopropylethylamine (0.16 mL, 0.89 mmol) were subsequently added, andthe mixture was stirred at rt overnight. EtOAc was added, and the solidswere isolated by vacuum filtration to give the title compound (42.7 mg,40%): HPLC MS RT=1.09 min, MH⁺=481.2; ¹H NMR (DMSO-d₆+2 drops TFA-d) δ:9.01 (2H, s), 8.04 (1H, d), 7.43 (1H, d), 4.54 (2H, m), 4.34 (2H, br t),4.23 (2H, m), 4.04 (2H, m), 4.00 (3H, s), 3.65 (2H, br t), 3.52 (2H, m),3.31 (2H, m), 3.18 (2H, m), 2.25 (2H, m).

Example 14 Preparation ofN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(150 mg, 0.21 mmol) was dissolved in DMF (2 mL), and6-(2-pyrrolidin-1-ylethyl)nicotinic acid (92 mg, 0.42 mmol) was added.PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (73 μL, 0.42 mmol)were subsequently added, and the mixture was stirred at rt overnight.The solids that formed were isolated by vacuum filtration and washedcopiously with ethyl acetate to give the title compound (81 mg, 69%):HPLC MS RT=1.05 min, MH⁺=562.2; ¹H NMR (DMSO-d₆+2 drops TFA-d) δ: 9.30(1H, s), 8.99 (0.5H, m), 8.50 (1H, d), 8.24 (0.5H, m), 8.06 (1H, d),7.53 (1H, d), 7.46 (1H, d), 4.55 (2H, t), 4.35 (2H, t), 4.24 (2H, t),4.01 (3H, s), 4.00 (2H, m), 3.68 (2H, m), 3.60 (4H, m), 3.51 (2H, m),3.29 (4H, m), 3.11 (2H, m), 2.26 (2H, m), 2.02 (3H, m), 1.87 (3H, m).

Example 15 Preparation of6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine(150 mg, 0.21 mmol) was dissolved in DMF (2 mL), and Intermediate 1 (60mg, 0.29 mmol) was added. PYBOP (217 mg, 0.42 mmol) anddiisopropylethylamine (73 μL, 0.42 mmol) were subsequently added, andthe mixture was stirred at rt overnight. The solids that formed wereisolated by vacuum filtration and washed copiously with ethyl acetate togive the title compound (80 mg, 69%): HPLC MS RT=1.74 min, MH⁺=548.2; ¹HNMR (DMSO-d₆+2 drops TFA-d) δ: 8.71 (1H, broad s), 8.39 (1H, broad s),8.03 (1H, d), 7.44 (1H, d), 7.04 (1H, broad s), 4.51 (2H, t), 4.34 (2H,t), 4.25 (2H, t), 4.13 (1H, m), 4.03 (2H, m), 4.00 (3H, s), 3.67 (2H,t), 3.52 (2H, d), 3.32 (2H, t), 3.15 (2H, t), 2.26 (2H, m), 2.03 (2H,m), 1.72 (2H, m), 1.61 (4H, m).

By using the methods described above for Examples 1-15, and bysubstituting the appropriate starting materials, Examples 16-104 foundin the table below were similarly prepared.

TABLE 1 LC-MS m/z Ex Structure Method 16

RT = 1.13 Min MH⁺ = 481.4 Route 4 17

RT = 1.12 Min MH⁺ = 479.1 Route 4 18

RT = 0.19 Min MH⁺ = 495.1 Route 4 19

RT = 0.21 Min MH⁺ = 519.1 Route 4 20

RT = 0.20 Min MH⁺ = 509.1 Route 4 21

RT = 0.23 Min MH⁺ = 465.2 Route 4 22

RT = 1.12 Min MH⁺ = 495.3 Route 4 23

RT = 1.03 Min MH⁺ = 451.4 Route 4 24

RT = 0.32 Min MH⁺ = 466.3 Route 1 25

RT = 0.34 Min MH⁺ = 481.3 Route 1 26

RT = 1.11 Min MH⁺ = 468.4 Route 1 27

RT = 1.54 Min MH⁺ = 494.3 Route 1 28

RT = 1.23 Min MH⁺ = 507.2 Route 1 29

RT = 1.95 Min MH⁺ = 550.2 Route 1 30

RT = 1.09 Min MH⁺ = 468.4 Route 1 31

RT = 1.13 Min MH⁺ = 494.4 Route 1 32

RT = 1.20 Min MH⁺ = 495.3 Route 1 33

RT = 1.69 Min MH⁺ = 558.2 Route 1 34

RT = 1.05 Min MH⁺ = 470.3 Route 1 35

RT = 1.00 Min MH⁺ = 437.2 Route 4 36

RT = 0.27 Min MH⁺ = 510.3 Route 2 37

RT = 0.24 Min MH⁺ = 444.1 Route 1 38

RT = 1.36 Min MH⁺ = 508.8 Route 1 39

RT = 1.07 Min MH⁺ 508.2 Route 1 40

RT = 1.34 Min MH⁺ = 525.2 Route 2 41

RT = 1.90 Min MH⁺ = 553.2 Route 2 42

RT = 1.17 Min MH⁺ = 439.1 Route 1 43

RT = 1.14 Min MH⁺ = 608.3 Route 2 44

RT = 1.66 Min MH⁺ = 539.2 Route 2 45

RT = 1.14 Min MH⁺ = 552.3 Route 2 46

RT = 1.04 Min MH⁺ = 438.1 Route 1 47

RT = 0.48 Min MH⁺ = 535.3 Route 2 48

RT = 0.33 Min MH⁺ = 564.3 Route 2 49

RT = 1.93 Min MH⁺ = 551.2 Route 2 50

RT = 1.03 Min MH⁺ = 549.1 Route 2 51

RT = 0.99 Min MH⁺ = 549.2 Route 2 52

RT = 0.98 Min MH⁺ = 549.2 Route 2 53

RT = 1.84 Min MH⁺ = 588.2 Route 2 54

RT = 1.48 Min MH⁺ = 560.2 Route 2 55

RT = 1.07 Min MH⁺ = 538.2 Route 2 56

RT = 2.10 Min MH⁺ = 530.1 Route 2 57

RT = 1.43 Min MH⁺ = 550.2 Route 2 58

RT = 0.31 Min MH⁺ = 409.2 Route 4 59

RT = 2.06 Min MH⁺ = 564.2 Route 2 60

RT = 1.90 Min MH⁺ = 548.2 Route 2 61

RT = 2.15 Min MH⁺ = 563.1 Route 2 62

RT = 1.94 Min MH⁺ = 533.1 Route 2 63

RT = 1.93 Min MH⁺ = 550.2 Route 2 64

RT = 1.04 Min MH⁺ = 478.1 Route 4 65

RT = 1.25 Min⁺ MH⁺ = 543.1 Route 2 66

RT = 1.53 Min MH⁺ = 537.0 Route 2 67

RT = 1.07 Min MH⁺ = 500.1 Route 2 68

RT = 1.02 Min MH⁺ = 451 Route 4 69

RT = 1.38 Min MH⁺ = 443.0 Route 4 70

RT = 1.03 Min MH⁺ = 423 Route 4 71

RT = 1.91 Min MH⁺ = 565.2 Route 2 72

RT = 1.11 Min MH⁺ = 534.2 Route 2 73

RT = 1.05 Min MH⁺ = 508.2 Route 2 74

RT = 1.15 Min MH⁺ = 463.1 Route 4 75

RT = 1.05 Min MH⁺ = 435.0 Route 4 76

RT = 1.09 Min MH⁺ = 449.0 Route 4 77

RT = 1.81 Min MH⁺ = 555.1 Route 2 78

RT = 1.76 Min MH⁺ = 483.0 Route 2 79

RT = 1.07 Min MH⁺ = 470.2 Route 2 80

RT = 1.28 Min MH⁺ = 514.3 Route 2 81

RT = 1.07 Min MH⁺ = 466.0 Route 2 82

RT = 1.89 Min MH⁺ = 381.4 Route 4 83

RT = 0.23 Min MH⁺ = 480.2 Route 1 84

RT = 0.21 Min MH⁺ = 465 Route 2 85

RT = 0.25 Min MH⁺ = 451.3 Route 4 86

RT = 1.19 Min MH⁺ = 465.2 Route 4 87

RT = 1.07 Min MH⁺ = 437.1 Route 4 88

RT = 1.04 Min MH⁺ = 423.2 Route 4 89

RT = 1.03 Min MH⁺ = 409.3 Route 4 90

RT = 1.28 Min MH⁺ = 495.2 Route 2 91

RT = 1.27 Min MH⁺ = 512.3 Route 2 92

RT = 0.95 Min MH⁺ = 395.1 Route 4 93

RT = 1.86 Min MH⁺ = 470.2 Route 2 94

RT = 1.74 Min MH⁺ = 499.1 Route 2 95

RT = 1.55 Min MH⁺ = 496.1 Route 2 96

RT = 0.61 Min MH⁺ = 454.2 Route 2 97

RT = 1.09 Min MH⁺ = 470.1 Route 2 98

RT = 0.35 Min MH⁺ = 485.3 Route 2 99

RT = 1.91 Min MH⁺ = 495.1 Route 2 100

RT = 1.38 Min MH⁺ = 495.1 Route 2 101

RT = 1.03 Min MH⁺ = 479.2 Route 4 102

RT = 1.60 Min MH⁺ = 522.1 Route 4 103

RT = 1.04 Min MH⁺ = 465.2 Route 2

Biological Evaluation

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.Stem Cells 1993, 11 (6), 528-35), taxotere (Bissery et al. Anti CancerDrugs 1995, 6 (3), 339), and topoisomerase inhibitors (Edelman et al.Cancer Chemother. Pharmacol. 1996, 37 (5), 385-93) were demonstratedwith the use of in vitro tumor proliferation assays.

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

Biological Assays

The effects of the compounds of the present invention were examined bythe following assays.

[Determination of IC₅₀ Values of Compounds in Kinase Assay of PI3Kα]

Chemicals and Assay Materials

Phosphatidylinositol (PtdIns) and phosphatidylserine (PtdSer) werepurchased from DOOSAN SERDARY RESEARCH LABORATORIES (Toronto, Canada).Recombinant truncated forms (ΔN1-108) of the human p110α and p110αsubunits of PI3K with N-terminal His₆-Tags were expressed in S.frugiperda 9 insect cells. Recombinant human PI3Kγ (full length humanPI3K p1 107 fused with a His₆-tag at the C-terminus expressed in S.frugiperda 9 insect cells) was obtained from ALEXIS BIOCHEMICALS(#201-055-C010; San Diego, Calif.). [γ³³P]ATP and unlabeled ATP werepurchased from AMERSHAM PHARMACIA BIOTECH (Buckinghamshire, UK) andROCHE DIAGNOSTICS (Mannheim, Germany), respectively. Scintillationcocktails and MicroScint PS™ were purchased from PACKARD (Meriden,Conn.). Maxisorp™ plates were purchased from NALGE NUNC INTERNATIONALK.K. (Tokyo, Japan). All other chemicals not further specified were fromWAKO PURE CHEMICALS (Osaka, Japan).

Solid-Phase Lipid Kinase Assay

To assess inhibition of PI3Kα by compounds, the Maxisorp™ plates werecoated with 50 μL/well of a solution containing 50 g/ml PtdIns and 50g/ml PtdSer dissolved in chloroform:ethanol (3:7). The plates weresubsequently air-dried by incubation for at least 2 hours in a fumehood. The reaction was set up by mixing 25 μL/well of assay buffer2×(100 mM MOPSO/NaOH, 0.2 M NaCl, pH 7.0, 8 mM MgCl₂, 2 mg/mL BSA (fattyacid-free)), and 7.5 ng/well PI3Kα in the lipid pre-coated plate. 100×test compounds were added in 2% DMSO. The reaction was started by adding20 μL/well of ATP mix (final 10 μM ATP; 0.05 μCi/well [γ³³P]ATP). Afterincubation at RT for 2 hours, the reaction was terminated by adding 50μl/well stop solution (50 mM EDTA, pH 8.0). The plate was then washedtwice with Tris-buffered saline (TBS, pH 7.4). MicroScint PS™ (PACKARD)scintillation mix was added at 100 μL/well, and radioactivity wascounted using a TopCount™ (PACKARD) scintillation counter.

The inhibition percent at each concentration of compound was calculated,and IC₅₀ values were determined from the inhibition of curve.

The following compounds displayed an average IC₅₀ of less than 10nanomolar in the p110α assay: Entries: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 13, 16, 18, 19, 20, 22, 23, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 42, 44, 45, 46, 51, 52, 54, 55, 58, 60, 63, 66, 68, 69,71, 73, 74, 75, 76, 78, 83, 85, 87, 88, 89, 92, 94, 100, 101 and 103.The following compounds displayed an average IC₅₀ of between 10nanomolar and 100 nanomolar in this assay: Entries: 14, 15, 17, 21, 25,26, 41, 43, 47, 49, 50, 53, 56, 57, 61, 62, 93 and 98. The followingcompounds displayed an average IC₅₀ of greater than 100 nanomolar inthis assay: Entries: 12, 24, 48 and 59.

[Isozyme Selectivity Test in PI3K]

Chemicals and Assay Materials

A recombinant truncated form (ΔN1-108) of the human p1103 subunit ofPI3K with an N-terminal His₆-Tag was expressed in S. frugiperda 9 insectcells. Recombinant human PI3Kγ (full length human PI3K p110γ fused witha His₆-tag at the C-terminus expressed in S. frugiperda 9 insect cells)was obtained from ALEXIS BIOCHEMICALS (#201-055-C010; San Diego,Calif.).

Determination of IC₅₀ Values of Compounds in Kinase Assays of PI3Kβ andPI3Kγ

Kinase assays using recombinant truncated p110β or the full length p110γwere performed in a similar manner as described in the part of[Determination of IC₅₀ values of compounds in kinase assay of PI3Kα]except that these isoforms were assayed using 7.5 ng and 25.0 ng ofprotein/well, respectively.

The following compounds displayed an average IC₅₀ of less than 10nanomolar in the p110β assay: Entries: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 13, 16, 18, 19, 20, 22, 23, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 42, 44, 45, 46, 51, 52, 54, 55, 58, 60, 63, 66, 68, 69,71, 73, 74, 75, 76, 78, 83, 85, 87, 88, 89, 92, 94, 100, 101 and 103.The following compounds displayed an average IC₅₀ of between 10nanomolar and 100 nanomolar in this assay: Entries: 14, 15, 17, 21, 25,26, 41, 43, 47, 49, 50, 53, 56, 57, 61, 62, 93 and 98. The followingcompounds displayed an average IC₅₀ of greater than 100 nanomolar inthis assay: Entries: 12, 24, 48 and 59.

[Determination of IC₅₀ Values of Compounds in Cell Based Assays of PI3KActivity]

Chemicals and Assay Materials

96-well collagen treated clear bottom/black sided Costar plates werepurchased from CORNING LIFE SCIENCES (Corning, N.Y.; at.#3904). GibcoRPMI medium (Cat.#11875), Biosource anti-phospho-AKT(Ser 473) antibody(Cat.#44-621G) and recombinant IGF-1 (Cat.#PHG0074) were purchased fromINVITROGEN (Carlsbad, Calif.). The secondary donkey anti-rabbit IgGhorse radish peroxidase conjugate (Cat. #NA934V) and ECLchemiluminesence reagent (Cat.#RPN2209) were purchased from AMERSHAM(Buckinghamshire, UK). Cell culture tested bovine serum albumin solution(35% in DPBS; Cat.#A7979) and all other chemicals were purchased fromSIGMA (St. Louis, Mo.). The Wallac Victor2 1420 Multilabel HTS Counterwas purchased from PERKINELMER (Wellesley, Mass.)

IGF-1 Induced AKT Phosphorylation Assay

To test inhibition of IGF-1 induced AKT phosphorylation by compounds,A549 cells (5×10⁴ cells/well) were seeded in 100 μL of 0.1% bovine serumalbumin (BSA) in RPMI medium in 96-well collagen treated clearbottom/black sided plates and incubated overnight at 37° C. in a 5% CO₂incubator. 10× compound solution (in 0.1% BSA in RPMI) was added to theplates and incubation at 37° C. was continued for 1 hour. All wells(except no IGF-1 controls) were then treated with 25 ng/ml IGF-1 for 10minutes at 37° C. in a 5% CO₂ incubator. Following removal of thesupernatants and washing with the wells with TBS (50 mM Tris pH 8.0containing 138 mM NaCL and 27 mM KCl), 200 L of 3.7% formaldehyde in TBSwas added to each well, and the plate was incubated at 4° C. for 10minutes. Supernatants were once again removed and replaced with 50 μLMethanol (−20° C.) and the plate incubated at 4° C. for 5 minutes. 200μL of 0.1% BSA in TBS was then added to each well and the plateincubated at room temperature for ½ hour. Supernatants were removed and50 μL of a solution comprising the primary anti-phospho-AKT(Ser 473)antibody diluted 1:250 in TBS containing 0.1% BSA was added to each well(except control/background wells). The plate was then incubated for 1½hour at room temperature. Supernatants were removed, each well waswashed 3 times with 200 μL TBS, and 100 μL of a solution containing thesecondary donkey anti-rabbit IgG antibody HRP-conjugate diluted 1:100 inTBS-T (TBS containing 0.1% triton). Plates were then incubated for 1hour at room temperature. After removing the secondary antibody, eachwell was washed 6 times with cold TBS-T, 100 μL of ECL was added to eachwell, and the plate was placed on an orbital shaker for 1 minute. Theplates were then read on a Wallac Victor2 1420 Multilabel HTS Counterusing the luminometry window (maximum light detection is measured at 428nM). IC₅₀ values were determined from the inhibition curve.

The following compounds displayed an average IC₅₀ of less than 100nanomolar in the A549 cell assay: Entries: 2, 3, 6, 7, 8, 10, 11, 13,16, 18, 19, 20, 21, 22, 23, 27, 28, 29, 31, 32, 33, 35, 37, 38, 39, 42,46, 47, 52, 60, 63, 66, 68, 69, 70, 71, 74, 75, 76, 77, 83, 85, 90, 91,94, 95, 99, 101 and 103. The following compounds displayed an averageIC₅₀ of between 100 nanomolar and 1000 nanomolar in this assay: Entries:1, 4, 5, 9, 30, 34, 36, 40, 41, 45, 51, 54, 55, 57, 58, 61, 62, 64, 67,72, 73, 78, 80, 82, 84, 86, 87, 88, 89, 93, 96, 97 and 100. Thefollowing compounds displayed an average IC₅₀ of greater than 1000nanomolar in this assay: Entries: 12, 14, 15, 24, 25, 26, 43, 44, 48,50, 53, 56, 59, 65, 79, 81, 92 and 98.

Mouse

To evaluate the in vivo anti-tumor effect of PI3K inhibitors, efficacystudies were conducted in the NCr athymic female mice (Taconic, N.Y.).Human carcinoma cells of various histological types were harvested frommid-log phase cultures using Trypsin-EDTA (Gibco). Cells were pelleted,rinsed twice, and resuspended in sterile HBSS (Hank's Balanced SaltSolution) to final concentration of 2.5×10⁶ cells/ml. Cells wereimplanted subcutaneously (s.c.) in a 0.2 ml volume (5×10⁶ cells) intothe right flank. When tumors reached an average size of ˜100-125 mg, themice were randomized, and treatment initiated. Each experimental groupconsisted of 10 mice and the dosing volume was 10 ml/kg body weight.Compounds were dissolved in a compatible vehicle for both intravenousand oral administration. For intravenous administration, mice are placedunder a heat lamp to warm for 5 minutes, then placed in a restrainingdevice and the tail vein injected with a sterile 27 gauge ½ inch needle.Oral dosing utilizes sterile disposable feeding needles (20 gauge/1½inches) from Popper and Sons, New Hyde Park, N.Y. Tumor growth wasmeasured with electronic calipers 2-3 times a week and tumor weight (mg)calculated according to the following formula: [length (mm)×width(mm)2]/2. Percent inhibition or tumor growth inhibition (TGI) iscalculated on days of measurement using the following formula: (100−meantumor value of treated (T)/mean tumor of control value (C)×100)=% T/C.Of note: the control used in the calculations is either the “untreatedcontrol” or “vehicle”, whichever provides the most conservativerepresentation of the data.

Rat

To evaluate the in vivo anti-tumor effect of PI3K inhibitors, efficacystudies were conducted in the HSD athymic female rats (Harlan, Id.).Human carcinoma cells of various histological types were harvested frommid-log phase cultures using Trypsin-EDTA (Gibco). Cells were pelleted,rinsed twice, and resuspended in sterile HBSS (Hank's Balanced SaltSolution) to final concentration of 2.5×10⁶ cells/ml. Cells wereimplanted subcutaneously (s.c.) in a 0.2 ml volume (5×106 cells) intothe right flank. When tumors reached an average size of ˜200-400 mg, therats were randomized, and treatment initiated. Each experimental groupconsisted of 10 nude rats. Compounds were dissolved in a compatiblevehicle for both intravenous and oral administration. For intravenousadministration of compound, rats were warmed under a heating lamp for 5minutes, then placed in a restraining device, and injected intravenouslyvia the tail vein using a dosing volume ranging from 2 mL/kg to 5 mL/kgwith a sterile 25 gauge needle. Oral dosing utilizes sterile disposablefeeding needles (18 gauge/2 inch) from Popper and Sons, New Hyde Park,N.Y. Tumor growth was measured with electronic calipers 2-3 times a weekand tumor weight (mg) calculated according to the following formula:[length (mm)×width (mm)2]/2. Percent inhibition or tumor growthinhibition (TGI) is calculated on days of measurement using thefollowing formula: (100−mean tumor value of treated (T)/mean tumor ofcontrol value (C)×100)=% T/C. Of note: the control used in thecalculations is either the “untreated control” or “vehicle”, whicheverprovides the most conservative representation of the data.

It is believed that one skilled in the art, using the preceedinginformation and information available in the art, can utilize thepresent invention to its fullest extent. Those skilled in the art willrecognize that the invention may be practiced with variations on thedisclosed structures, materials, compositions and methods withoutdeparting from the spirit or scope of the invention as it is set forthherein and such variations are regarded as within the ambit of theinvention. The compounds described in the examples are intended to berepresentative of the invention, and it will be understood that thescope of the invention is not limited by the scope of the examples. Thetopic headings set forth above are meant as guidance where certaininformation can be found in the application, but are not intended to bethe only source in the application where information on such topics canbe found. All publications and patents cited above are incorporatedherein by reference.

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What is claimed is:
 1. A compound having the formula:

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein: R¹ is —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′)); R² isa heteroaryl optionally substituted with 1, 2 or 3 R⁶ groups; R³ isalkyl or cycloalkyl; R⁴ is hydrogen, hydroxy or alkoxy; R⁵ and R^(5′)may be the same or different and are independently, hydrogen, alkyl,cycloalkylalklyl, or alkoxyalkyl or R⁵ and R^(5′) may be taken togetherwith the nitrogen atom to which they are bound to form a 3-7 memberednitrogen containing heterocyclic ring optionally containing at least oneadditional heteroatom selected from oxygen, nitrogen or sulfur and whichmay be optionally substituted with 1 or more R^(6′) groups, or R⁴ and R⁵may be taken together with the atoms to which they are bound to form a5-6 membered nitrogen containing heterocyclic ring optionally containing1 or more nitrogen, oxygen or sulfur atoms and which may be optionallysubstituted with 1 or more R^(6′) groups; each occurrence of R⁶ may bethe same or different and is independently halogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalklyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, alkyl-OR⁷,alkyl-SR⁷, alkyl-N(R⁷)(R^(7′)), alkyl-COR⁷, —CN, —COOR⁷,—CON(R⁷)(R^(7′)), —OR⁷, —SR⁷, —N(R⁷)(R^(7′)), or —NR⁷COR⁷ each of whichmay be optionally substituted with 1 or more R⁸ groups; each occurrenceof R^(6′) may be the same or different and is independently alkyl,cycloalkylalklyl, or alkyl-OR⁷; each occurrence of R⁷ and R^(7′) may bethe same or different and is independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl,heteroaryl, heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;each occurrence of R⁸ is independently nitro, hydroxy, cyano, formyl,acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl; n is aninteger from 1-4 and m is an integer from 0-4 with the proviso that whenR⁴ and R⁵ are taken together with the atoms to which they are bound toform a 3-7 membered nitrogen containing ring, n+m≦4.
 2. The compound ofclaim 1, wherein R² is a nitrogen containing heteroaryl optionallysubstituted with 1, 2 or 3 R⁶ groups.
 3. The compound of claim 1,wherein R⁵ and R^(5′) are independently alkyl.
 4. The compound of claim1, wherein R⁵ and R^(5′) are taken together with the nitrogen atom towhich they are bound to form a 5-6 membered nitrogen containingheterocyclic ring containing at least one additional heteroatom selectedfrom oxygen, nitrogen or sulfur and which may be optionally substitutedwith 1 or more R^(6′) groups.
 5. The compound of claim 1, wherein R⁴ ishydroxy.
 6. The compound of claim 1, wherein R⁴ and R⁵ are takentogether with the atoms to which they are bound to form a 5-6 memberednitrogen containing heterocyclic ring optionally containing 1 or morenitrogen, oxygen or sulfur atoms and which may be optionally substitutedwith 1 or more R^(6′) groups.
 7. The compound of claim 1, wherein R³ ismethyl.
 8. The compound of claim 1, wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, ineach case unsubstituted or substituted with 1, 2 or 3 R⁶ groups.
 9. Thecompound of claim 2, wherein R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted orsubstituted with 1, 2 or 3 R⁶ groups.
 10. The compound of claim 1,having the formula:


11. The compound of claim 10, wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, ineach case unsubstituted or substituted with 1, 2 or 3 R⁶ groups.
 12. Thecompound of claim 11, wherein R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted orsubstituted with 1, 2 or 3 R⁶ groups.
 13. The compound of claim 1 havingthe formula:


14. The compound of claim 13, wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, ineach case unsubstituted or substituted with 1, 2 or 3 R⁶ groups.
 15. Thecompound of claim 14, wherein R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted orsubstituted with 1, 2 or 3 R⁶ groups.
 16. The compound of claim 1 havingthe formula:


17. The compound of claim 16, wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, ineach case unsubstituted or substituted with 1, 2 or 3 R⁶ groups.
 18. Thecompound of claim 17, wherein R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted orsubstituted with 1, 2 or 3 R⁶ groups.
 19. The compound of claim 1 havingthe formula:


20. The compound of claim 19, wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, ineach case unsubstituted or substituted with 1, 2 or 3 R⁶ groups.
 21. Thecompound of claim 20, wherein R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted orsubstituted with 1, 2 or 3 R⁶ groups.
 22. The compound of claim 19wherein R^(5′) is alkyl.
 23. The compound of claim 1 having the formula:


24. The compound of claim 23, wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, ineach case unsubstituted or substituted with 1, 2 or 3 R⁶ groups.
 25. Thecompound of claim 24, wherein R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted orsubstituted with 1, 2 or 3 R⁶ groups.
 26. The compound of claim 23wherein R^(5′) is alkyl.
 27. The compound according to claim 1, whereinsaid compound is selected from:N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide;N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide1-oxide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[8-(2-hydroxy-3-morpholin-4-ylpropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{7-methoxy-8-[3-(3-methylmorpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{2-[4-(cyclobutylmethyl)morpholin-2-yl]ethoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(7-methoxy-8-{2-[4-(2-methoxyethyl)morpholin-2-yl]ethoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{8-[(4-ethylmorpholin-2-yl)methoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-(7-methoxy-8-{[4-(2-methoxyethyl)morpholin-2-yl]methoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{7-methoxy-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-4-carboxamide;rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-6-methylnicotinamide;rel-6-acetamido-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-5-carboxamide;6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methylnicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methylpyrimidine-5-carboxamide;6-amino-5-bromo-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-5-carboxamide;N-[7-methoxy-8-(morpholin-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-{[2-(dimethylamino)ethyl]amino}-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-1,3-thiazole-5-carboxamide;rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;2-[(2-hydroxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-methoxypropyl)amino]pyrimidine-5-carboxamide;2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-morpholin-4-ylpropyl)amino]pyrimidine-5-carboxamide;2-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;6-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-pyrrolidin-1-ylpyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-morpholin-4-ylpyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-piperazin-1-ylnicotinamidehydrochloride;6-[(3S)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidehydrochloride hydrate;6-[(3R)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidehydrochloride;6-[(4-fluorobenzyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(2-furylmethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(1H-pyrrol-1-yl)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-morpholin-4-ylnicotinamide;N-{7-methoxy-8-[3-(methylamino)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamideN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2,2,2-trifluoroethoxy)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(trifluoromethyl)nicotinamide;6-(isobutyrylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{7-methoxy-8-[3-(4-methylpiperazin-1-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-{[(methylamino)carbonyl]amino}-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-{[(methylamino)carbonyl]amino}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-6-methylnicotinamide;6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-pyrrolidin-1-ylnicotinamide;6-(dimethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-piperidin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(2-pyrrolidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(2-piperidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-{[(ethylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-fluoro-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-4-carboxamide;2-(ethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrazine-2-carboxamide;N-[8-(2-aminoethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;N-{8-[3-(diethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(diisopropylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(diethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylthio)pyrimidine-5-carboxamide;N-[8-(3-aminopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidetrifluoroacetate;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-2-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;2-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-3-furamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-3-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methyl-1,3-thiazole-4-carboxamide;6-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;6-(acetylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;and physiologically acceptable salts, solvates, hydrates, andstereoisomers thereof.
 28. The compound according to claim 1, whereinsaid compound is selected from:N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;and physiologically acceptable salts, solvates, hydrates andstereoisomers thereof.
 29. A pharmaceutical composition comprising acompound according to claim 1 and a pharmaceutically acceptable diluentor carrier.
 30. The pharmaceutical composition of claim 29, wherein thecompound is present in a therapeutically effective amount.
 31. Thepharmaceutical composition of claim 29, further comprising at least onefurther active compound.
 32. The pharmaceutical composition of claim 29,wherein the further active compound is an anti-hyper-proliferative,anti-inflammatory, analgesic, immunoregulatory, diuretic,anti-arrhythmic, anti-hypercholesterolemic, anti-diabetic,anti-dyslipidemia, anti-diabetic or antiviral agent.
 33. Thepharmaceutical composition of claim 32, wherein the further activecompound is gemcitabine, paclitaxel, cisplatin, carboplatin, sodiumbutyrate, 5-FU, doxirubicin, tamoxifen, etoposide, trastumazab,gefitinib, intron A, rapamycin, 17-AAG, U0126, insulin, an insulinderivative, a PPAR ligand, a sulfonylurea drug, an α-glucosidaseinhibitor, a biguanide, a PTP-1B inhibitor, a DPP-IV inhibitor, a11-beta-HSD inhibitor, GLP-1, a GLP-1 derivative, GIP, a GIP derivative,PACAP, a PACAP derivative, secretin, secretin derivative, aldesleukin,alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi,altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine,anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin,5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasoneacetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol,etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim,finasteride, fligrastim, floxuridine, fluconazole, fludarabine,5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lentinan sulphate, letrozole, leucovorin,leuprolide, leuprolide acetate, levamisole, levofolinic acid calciumsalt, levothroid, levoxyl, lomustine, lonidamine, marinol,mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrolacetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate,metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide,nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin,picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab,roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine,sizofuran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin,tasonermin, tastolactone, taxotere, teceleukin, temozolomide,teniposide, testosterone propionate, testred, thioguanine, thiotepa,thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine,valrubicin, vesnarinone, vinblastine, vincristine, vindesine,vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran,ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene,asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin,CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate,decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,eflornithine, exatecan, fenretinide, histamine dihydrochloride,histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene,minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin,neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxelpolyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549,raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol,T-138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine,tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar,vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acidor combinations thereof.
 34. A packaged pharmaceutical compositioncomprising a container, the pharmaceutical composition of claim 29 andinstructions for using the pharmaceutical composition to treat a diseaseor condition in a mammal.
 35. A method of inhibitingphosphotidylinositol-3-kinase in cells comprising contacting a cell withone or more compounds of claim
 1. 36. A method of treating a disordermediated by phosphotidylinositol-3-kinase inhibition in a mammalcomprising administering to a mammal in need thereof, a therapeuticallyeffective amount of one or more compounds of claim
 1. 37. The method ofclaim 36, wherein the disorder mediated by phosphotidylinosito-3-kinaseis an angiogenic disorder, an inflammatory disorder, an autoimmunedisorder, a cardiovascular disorder, a neurodegenerative disorder, ametabolic disorder, a nociceptive disorder, an ophthalmic disorder, apulmonary disorder, or a renal disorder.
 38. The method of claim 37,wherein the cardiovascular disorder is thrombosis, pulmonaryhypertension, cardiac hypertrophy, atherosclerosis or heart failure. 39.The method of claim 37, wherein the inflammatory disorder is COPD. 40.The method of claim 37, wherein the angiogenic disorder diabeticretinopathy, ischemic retinal-vein occlusion, retinopathy ofprematurity, macular degeneration, neovascular glaucoma, psoriasis,retrolental fibroplasias, angiofibroma, inflammation, rheumatoidarthritis, restenosis, in-stent restenosis, or vascular graftrestenosis.
 41. A method of treating a hyperproliferative disordermediated by phosphotidylinositol-3-kinase in a mammal comprisingadministering to a mammal in need thereof, a therapeutically effectiveamount of one or more compounds of claim
 1. 42. The method of claim 41,wherein the hyperproliferative disorder is cancer.
 43. The method ofclaim 42, wherein the cancer is a cancer of the breast, respiratorytract, brain, reproductive organs, digestive tract, urinary tract, eye,liver, skin, head and neck, thyroid, parathyroid or a distant metastasisof a solid tumor.
 44. The method of claim 42 wherein the cancer is alymphoma, sarcoma, or leukemia.
 45. The compound of claim 1, wherein—N(R⁵)(R^(5′)) is morpholinyl; R² is pyridine, pyridazine, pyrimidine,pyrazine, pyrole, oxazole, thiazole, furan or thiophene, in each caseunsubstituted or substituted with 1, 2 or 3 R⁶ groups; and R³ is methyl.46. The method of claim 42 wherein the cancer is colorectal cancer. 47.The compound of claim 1, wherein —N(R⁵)(R^(5′)) is morpholinyl; R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, orthiazole, in each case unsubstituted or substituted with 1, 2 or 3 R⁶groups; and R³ is methyl.